Parkinson's Disease: From Pathogenesis To Pharmacogenomics: Molecular Sciences

International Journal of
Molecular Sciences
Review
Parkinson’s Disease: From Pathogenesis
to Pharmacogenomics
Ramón Cacabelos
EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine,
15165-Bergondo, Corunna, Spain; rcacabelos@euroespes.com
Academic Editor: Sabrina Angelini

Received: 5 January 2017; Accepted: 20 February 2017; Published: 4 March 2017
Abstract: Parkinson’s disease (PD) is the second most important age-related neurodegenerative
disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41
per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of
age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor,
and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several
decades before the onset of the motor symptoms. Potential risk factors include environmental
toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects.
Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons
in the substantia nigra pars compacta, with widespread involvement of other central nervous
system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic,
epigenetic and environmental factors lead to conformational changes and deposits of key
proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation
of mitochondrial function and oxidative stress. Conventional pharmacological treatments
for PD are dopamine precursors (levodopa, L-DOPA, L-3,4 dihidroxifenilalanina), and other
symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine,
cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO)
inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone,
tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off
phenomenon”, with additional psychomotor and autonomic complications. In order to minimize
these clinical complications, novel compounds have been developed. Novel drugs and bioproducts
for the treatment of PD should address dopaminergic neuroprotection to reduce premature
neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical
changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients,
personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.
Keywords: adrenaline; antiparkinsonian drugs; Atremorine; dopamine; genomics; growth hormone;

noradrenaline; Parkinson’s disease; pharmacogenetics; prolactin
1. Introduction
Since 1915, over 85,000 papers have been published on Parkinson’s disease (PD) and related
disorders in the international literature. The clinical entity described by James Parkinson (1755–1824) in
1817 as “paralysis agitans” in his “Assay on the Shaking Palsy” is at present the second most important
neurodegenerative disorder in the elderly population, after Alzheimer’s disease.
With a prevalence ranging from 35.8 per 100,000 to 12,500 per 100,000 and annual incidence
estimates ranging from 1.5 per 100,000 to 346 per 100,000 in different countries [1–3], PD is becoming
a major age-related problem of health [4,5]. Meta-analysis of the worldwide data indicates a rising
Int. J. Mol. Sci. 2017, 18, 551; doi:10.3390/ijms18030551 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2017, 18, 551 2 of 28
prevalence of PD with age (41 per 100,000 at 40–49 years; 107 at 50–59 years; 173 at 55–64 years;
428 at 60–69 years; 425 at 65–74 years; 1087 at 70–79 years; and 1903 per 100,000 at over age 80), also
reflecting a characteristic distribution by geographic location (a prevalence of 1601 per 100,000 in
patients from North America, Europe and Australia, and a prevalence of 646 per 100,000 in Asian
patients [6]. Parkinson’s disease is more prevalent in males (1729 per 100,000, >65 years) than in
females (1644 per 100,000), with a peak prevalence in the age group of ≥90 years (4633 cases per
100,000), and a mean prevalence of 1680 per 100,000 in people over 65 years of age [7]. Prevalence
and incidence male/female (M/F) ratios increase by 0.05 and 0.14, respectively, per 10 years of age.
Incidence is similar in men and women under 50 years (M/F ratio < 1.2), and over 1.6 times higher in
men than women above 80 years [8]. Furthermore, PD coexists with dementia in over 25% of the cases
and with depression in over 30% of the cases in some countries [7].
The diagnosis of PD basically relies on clinical data characterized by rigidity, resting tremor,
bradykinesia and postural imbalance. Although the primary cause of neurodegenerative disorders
and the pathogenic mechanisms underlying protein conformational changes and premature
neurodegeneration are unknown, recent advances in genomic medicine (structural and functional
genomics, epigenetics, transcriptomics, proteomics, metabolomics, pharmacogenomics) have greatly
contributed to better understand the complex processes responsible for age-related neuronal death in
neurodegenerative disorders [9–14].
From a therapeutic perspective, the introduction of levodopa (L-DOPA) in the 1960s represented
a breakthrough in the treatment of PD, and it continues to be the most effective symptomatic
therapy in Parkinsonian disorders [15]. However, the chronic administration of L-DOPA and other
antiparkinsonian drugs currently causes severe side effects that deserve special attention by the medical
community. In this regard, novel compounds devoid of psychomotor, biochemical, neuropsychiatric
and autonomic complications are under experimental scrutiny in preclinical studies and clinical
trials [16–18].
A substantial component of drug pharmacokinetics and pharmacodynamics in PD can be
attributed to the pharmacogenetic profile of each patient [19] (Table 1). Pathogenic, mechanistic,
metabolic, transporter and pleiotropic genes associated with the pharmacogenetic outcome are
determinant in the optimization of PD therapeutics [17,18].
Important issues to take into consideration for the appropriate management of PD are the
following: (i) identification of environmental factors responsible for PD-related neurotoxicity;
(ii) characterization of the population at risk for developing PD with predictive biomarkers;
(iii) implementation of preventive programs; (iv) optimization of therapeutics with conventional
antiparkinsonian drugs; (v) development of novel compounds with specific neuroprotective effects on
the dopaminergic system and devoid of severe side effects; and (vi) incorporation of pharmacogenetic
procedures for a personalized treatment of PD patients [17–20].
Int. J. Mol. Sci. 2017, 18, 551 3 of 30
Int. J. Mol. Sci. 2017, 18, 551 Table 1. Pharmacogenetics of antiparkinsonian drugs. 3 of 28
Int. J. Mol. Sci. 2017, 18, 551 3 of 30
Dopamine Precursors
Drug Properties
Table 1. Pharmacogenetics of antiparkinsonian drugs. Pharmacogenetics
Table 1. Pharmacogenetics of antiparkinsonian drugs.
Name: Carbidopa; 28860-95-9; Lodosyn.
Dopamine Precursors
IUPAC Name: Benzenepropanoic acid, α-hydrazino-3,4-
Drug Properties Pharmacogenetics
dihydroxy-α-methyl-, monohydrate,(S) Dopamine Precursors
Name: Carbidopa; 28860-95-9; Lodosyn.
Drug Molecular Formula: C10H14N2O4 H2O Properties Pharmacogenetics
IUPAC Name: Benzenepropanoic acid, α-hydrazino-3,4-
Molecular
Name: Weight:
Carbidopa; 244.24 g/mol Lodosyn.
28860-95-9;
dihydroxy-α-methyl-, monohydrate,(S) Pathogenic genes: BDNF, PARK2
Mechanism:
IUPAC Name: Carbidopa is a peripheral
Benzenepropanoic acid,decarboxylase inhibitor
Molecular Formula: C10H14N2O4 H2O Mechanistic genes: DRD2, OPRM1
CH3 little or no pharmacological activitymonohydrate,(S)
withα-hydrazino-3,4-dihydroxy-α-methyl-, when given alone in
.HO Molecular Weight:
Molecular 244.24
Formula: C10g/mol
H14 N2 O4 H2 O Metabolic genes:
usualMolecular
doses. ItWeight:
inhibits244.24
the peripheral decarboxylation of levodopa Pathogenic genes: BDNF, PARK2
2
Mechanism: Carbidopa is a peripheral
g/mol decarboxylase inhibitor COMT,
Substrate:genes:
Pathogenic DDC
BDNF, PARK2
to dopamine. At the same time, reduced peripheral formation of
Mechanism: Carbidopa is a peripheral decarboxylase inhibitor with little Mechanistic Mechanistic genes: DRD2,
genes: DRD2,OPRM1
OPRM1
CH3 with little or no pharmacological activity when given alone in Pleiotropic genes: ACE, ACHE
.HO dopamine reduces peripheral
or no pharmacological side
activity when effects,
givennotably nausea
alone in usual or It inhibitsMetabolic
doses. genes:
Metabolic genes:
usualthe
doses. It inhibits the peripheral decarboxylation of levodopa
2
vomiting, and cardiac
peripheral arrhythmias,
decarboxylation althoughtothe
of levodopa dyskinesias
dopamine. At theand
same Substrate:
Substrate: COMT,
COMT, DDCDDC
to dopamine.
time, reducedAt the same time,
peripheral reduced
formation peripheral
of dopamine formation
reduces of side Pleiotropic genes: ACE, ACHE
peripheral
adverse mental effects associated with levodopa therapy tend to Pleiotropic genes: ACE, ACHE
dopamine
effects,reduces peripheral
notably nausea side effects,
or vomiting, notably
and cardiac nausea oralthough the
arrhythmias,
develop earlier.and adverse mental effects associated with levodopa therapy
vomiting, and cardiac arrhythmias, although the dyskinesias and
dyskinesias
Effect: Antiparkinsonian
tend to develop earlier.agents. Dopamine precursors.
adverse mental effects associated
agents.with levodopa therapy tend to
Name: Levodopa;
Effect: 59-92-7; Levodopa;
Antiparkinsonian L-DOPA;
Dopamine Dopar; Bendopa;
precursors.
develop earlier. Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2
Dopasol; 3,4-dihydroxy-L-phenylalanine; Madopar. Bendopa; Dopasol;
Name: Levodopa; 59-92-7; Levodopa; L -DOPA; Dopar;
Effect: Antiparkinsonian agents. Dopamine precursors. Mechanistic genes: CCK, CCKAR, CCKBR, DRD1,
IUPAC Name: L-Tyrosine-3-hydroxy
3,4-dihydroxy- L -phenylalanine; Madopar.
Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2
Name: Levodopa;
IUPAC Name: L59-92-7; Levodopa; L-DOPA; Dopar; Bendopa;
-Tyrosine-3-hydroxy DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B,
Molecular Formula: C 9H11NO4 Pathogenic genes:
Mechanistic ANKK1,
genes: BDNF, CCKBR,
CCK, CCKAR, LRRK2,DRD1,
PARK2DRD2, DRD3,
Dopasol; 3,4-dihydroxy-
Molecular Formula: CL9 H -phenylalanine;
11 NO4 Madopar. HCRT, HOMER1, LMO3, GRIN2B,
OPRM1
Molecular Weight: 197.19 g/mol Mechanistic
DRD4, genes:
DRD5, CCK, CCKAR, HCRT,
GRIN2A, CCKBR, DRD1, LMO3, OPRM1
HOMER1,
IUPAC Name:Weight:
Molecular L-Tyrosine-3-hydroxy
197.19 g/mol Metabolic genes:
Metabolic genes:
Mechanism:
Mechanism: Levodopa
Levodopa circulates
circulatesin inthe
the plasma
plasma totothe
theblood–brain–barrier,
blood– DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B,
Molecular Formula:to C9H11 NO4 Substrate:
Substrate: COMT,
COMT, CYP1A2,
CYP1A2, CYP2B6,
CYP2B6, CYP2C19, CYP2D6, CYP3A4,
brain–barrier, where itbecrosses,
where it crosses, convertedto beby converted by striatal
striatal enzymes enzymes HCRT,
to dopamine. HOMER1, LMO3, OPRM1
Molecular Weight:
Carbidopa 197.19
inhibits g/mol plasma breakdown of levodopa by CYP2C19,
the peripheral
CYP3A5,CYP2D6,
DBH, DDC, CYP3A4,
G6PD, CYP3A5,
MAOB, TH,DBH, DDC,
UGT1A1, UGT1A9
to dopamine. Carbidopa inhibits the peripheral plasma Metabolic genes:
Transporter genes: SLC22A1, SLC6A3
Mechanism:
inhibitingLevodopa circulates
its carboxylation, and in the plasma
thereby to available
increases the blood– levodopa at G6PD, MAOB, TH, UGT1A1, UGT1A9
breakdown of levodopa by inhibiting its carboxylation, and Pleiotropic COMT,
Substrate:genes: CYP1A2,
ACE, ACHE CYP2B6,
brain–barrier, where it crosses, to be converted by striatal enzymes Transporter genes: SLC22A1, SLC6A3
the blood–brain–barrier.
thereby increases
Effect: available agents.
Antiparkinsonian levodopa at the blood–brain–barrier.
Dopamine precursors. CYP2C19, CYP2D6, CYP3A4, CYP3A5, DBH, DDC,
Int. J. Mol. Sci. 2017, 18, 551 to dopamine. Carbidopa inhibits the peripheral plasma Pleiotropic genes: ACE, ACHE 4 of 30
Effect: Antiparkinsonian agents. Dopamine precursors. Agonists G6PD, MAOB, TH, UGT1A1, UGT1A9
breakdown of levodopa by inhibiting its carboxylation, Dopaminergic and
Dopaminergic Agonists Transporter genes: SLC22A1, SLC6A3
Drug Name: Amantadine;
thereby increases available768-94-5; Amantadine;
levodopa Symmetrel; PK-Merz;
at the blood–brain–barrier.
Properties Pharmacogenetics
Drug Properties Pleiotropic genes: ACE, ACHE
Pharmacogenetics
Amantadina.
Name: Amantadine; 768-94-5; agents.Amantadine;
Dopamine precursors.
Symmetrel; PK-Merz; Pathogenic genes: PARK2
IUPAC Name: Tricyclo[3.3.1.13,7]decan-1-amine,
Amantadina. Dopaminergichydrochloride
Agonists Mechanistic genes: CCR5, CXCR4, DRD1, DRD2,
Pathogenic genes: PARK2
Molecular
IUPACFormula: C10H17NHCl GRIN3A
Name: Tricyclo[3.3.1.1 3,7 ]decan-1-amine, hydrochloride
Mechanistic genes: CCR5, CXCR4, DRD1, DRD2, GRIN3A
Molecular Formula: C10 H17 NHCl
Molecular Weight: 187.71 g/mol Metabolic genes:
Metabolic genes:
Molecular Weight: 187.71 g/mol
Mechanism:
Mechanism: Antiparkinsonian
Antiparkinsonianactivityactivitymay
may be dueto
be due toinhibition
inhibition of of Substrate:
Substrate: COMT,
COMT, CYP1A2,
CYP1A2, CYP2B6,
CYP2B6, CYP2C19, CYP2D6, CYP3A4,
CYP3A5, DDC, UGT1A1, UGT1A9
dopamine
dopamine reuptake
reuptakeintointopresynaptic
presynapticneurons
neurons or orby
byincreasing
increasing dopamineCYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC,
Transporter genes: SLC22A1
dopamine
releaserelease from presynaptic
from presynaptic fibers. fibers. UGT1A1, UGT1A9
Effect: Antiparkinsonian agents; Adamantanes; Dopamine
Effect: Antiparkinsonian agents; Adamantanes; Dopamine agonists. Transporter genes: SLC22A1
agonists.
Pathogenic genes: PARK2
Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin;
Mechanistic genes: ADRA2A, ADRA2B, ADRA2C,
Apokinon; Apokyn; Apomorfina.
CALY, DRD1, DRD2, DRD3, DRD4, DRD5,
IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7-
HTR1A, HTR1B, HTR1D, HTR2A, HTR2B, HTR2C
tetrahydro-6-methyl-hydrochloride,hemihydrate.
Metabolic genes:
Molecular Formula: C17H17NO2HCl1/2H2O
Substrate: COMT, CYP1A2 (minor), CYP2B6,
CYP2C9 (minor), CYP2C19 (minor), CYP2D6,
Mechanism: Stimulates postsynaptic D2-type receptors within the
CYP3A4 (minor), CYP3A5, DDC, UGT1A1,
caudate putamen in the brain.
UGT1A9
Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine
Inhibitor: CYP1A2 (weak), CYP2C19 (weak),
receptor agonists.
CYP3A4 (weak)
Name: Bromocriptine; 25614-03-3; Parlodel; Pravidel; Cycloset;
Pathogenic genes: ANKK1, BDNF, GSK3B, LRRK2
Corpadel; Broman; Bromocriptina.
Mechanistic genes: ABCB1, AKT1, BDNF, CCK,
Int. J. Mol. Sci. 2017, 18, 551 4 of 30
Name: Amantadine; 768-94-5; Amantadine; Symmetrel; PK-Merz;
Amantadina.
Name: Amantadine; 768-94-5; Amantadine; Symmetrel; PK-Merz; Pathogenic genes: PARK2
IUPAC Name: Tricyclo[3.3.1.13,7]decan-1-amine, hydrochloride
Amantadina. Mechanistic CCR5, CXCR4, DRD1, DRD2,
genes:PARK2
Pathogenic genes:
Molecular
IUPAC Name:Formula: C10H17NHCl
Tricyclo[3.3.1.1 3,7]decan-1-amine, hydrochloride GRIN3A
Mechanistic genes: CCR5, CXCR4, DRD1, DRD2,
Molecular Formula:
Molecular Weight: 187.71
C10H17g/mol
NHCl Metabolic genes:
GRIN3A
Int. J. Mol. Sci. 2017, 18, 551 Mechanism: Antiparkinsonian COMT, CYP1A2, CYP2B6, 4 of 28
Molecular Weight: 187.71 g/molactivity may be due to inhibition of Substrate:
Metabolic genes:
dopamine reuptake
Mechanism: into presynaptic
Antiparkinsonian neurons
activity may beordue
by to
increasing
inhibition of CYP2C19, CYP2D6,
Substrate: COMT,CYP3A4, CYP3A5,
CYP1A2, DDC,
CYP2B6,
dopamine
dopamine release
reuptakefrom
intopresynaptic
presynapticfibers.
neurons or by increasing UGT1A1, UGT1A9
CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC,
dopamine agents; Adamantanes;
release from presynaptic fibers. TableDopamine
1. Cont. Transporter
UGT1A1, genes: SLC22A1
UGT1A9
agonists.
Effect: Antiparkinsonian agents; Adamantanes; Dopamine Transporter genes: SLC22A1
agonists. Dopaminergic Agonists Pathogenic genes: PARK2
Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin;
Mechanistic ADRA2A,
genes:PARK2
Pathogenic genes: ADRA2B, ADRA2C,
Drug Apokinon; Apokyn; Apomorfina.
Name: Apomorphine;
Properties
58-00-4; Apomorhin; Apo-go; Apofin;
Pharmacogenetics
CALY, DRD1,
Mechanistic DRD2,
genes: DRD3, DRD4,
ADRA2A, ADRA2B, DRD5,
ADRA2C,
IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol,
Apokinon; Apokyn; Apomorfina.
Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; 5,6,6a,7-
Apofin; Apokinon;
HTR1A,
CALY, HTR1B,
DRD1,
Pathogenic HTR1D,
DRD2,
genes: HTR2A,
DRD3,
PARK2 DRD4, HTR2B,
DRD5,HTR2C
tetrahydro-6-methyl-hydrochloride,hemihydrate.
IUPAC
Apokyn; Apomorfina.
Name: 4H-dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7- genes: HTR1D, HTR2A, HTR2B, HTR2CCALY, DRD1,
Mechanistic
Metabolic
HTR1A,
genes: ADRA2A, ADRA2B, ADRA2C,
DRD2,HTR1B,
IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol,
Molecular Formula: C17H17NO2HCl1/2H2O
tetrahydro-6-methyl-hydrochloride,hemihydrate. DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, HTR2A,
5,6,6a,7-tetrahydro-6-methyl-hydrochloride,hemihydrate. Substrate:
Metabolic genes:COMT, CYP1A2 (minor), CYP2B6,
Molecular
Molecular Weight:
Formula: 312.79
C17CH1717g/mol
NO 2HCl1/2H 2O2 O
HTR2B, HTR2C
Molecular Formula: H 17 NO 2 HCl1/2H CYP2C9 (minor),
Substrate:
Metabolic CYP2C19
COMT, CYP1A2
genes: (minor), CYP2D6,
(minor), CYP2B6,
Mechanism:
Molecular
Molecular Stimulates
Weight: 312.79
Weight: postsynaptic
312.79 g/mol
g/mol D2-type receptors within the
CYP3A4
CYP2C9 (minor),
(minor),
Substrate: CYP3A5,
CYP2C19
COMT, CYP1A2DDC, UGT1A1,
(minor),
(minor), CYP2D6,
CYP2B6, CYP2C9 (minor),
caudate putamen
Mechanism: in the
Stimulates brain.
postsynaptic D -type
Mechanism: Stimulates postsynaptic D2-type receptors within the
2 receptors within the caudate
putamen in the brain. UGT1A9
CYP2C19 (minor), CYP2D6, CYP3A4 (minor), CYP3A5, DDC,
CYP3A4 (minor), CYP3A5, DDC, UGT1A1,
Effect:
caudate Antiparkinsonian
putamen agents; Non-ergot-derivative dopamine
in the brain. UGT1A1, UGT1A9
Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Inhibitor:
UGT1A9 CYP1A2 (weak), CYP2C19 (weak),
receptor
Effect: agonists.
Antiparkinsonian agents; Non-ergot-derivative dopamine Inhibitor: CYP1A2 (weak), CYP2C19 (weak), CYP3A4 (weak)
receptor agonists. CYP3A4 (weak)CYP1A2 (weak), CYP2C19 (weak),
Inhibitor:
receptor agonists.
Name:Name: Bromocriptine;
Bromocriptine; 25614-03-3;
25614-03-3;Parlodel;
Parlodel; Pravidel; Cycloset;
Pravidel; Cycloset; Corpadel;CYP3A4 (weak)
Pathogenic genes: ANKK1, BDNF, GSK3B, LRRK2
Corpadel;
Name:
Broman; Broman;
Bromocriptine; Bromocriptina.
Bromocriptina.
25614-03-3; Parlodel; Pravidel; Cycloset;
IUPAC Name: Ergotaman-30 -60 -18-trione, 2-bromo-120 -hydroxy- Mechanisticgenes:
Pathogenic ABCB1, BDNF,
genes:ANKK1, AKT1, BDNF,
GSK3B,CCK,
LRRK2
IUPAC
Corpadel; Name: Ergotaman-3′-6′-18-trione,
Broman; Bromocriptina.
20 -(1-methylethyl)-5
2-bromo-12′-hydroxy-2′-
0 -(2-methylpropyl),monomethanesulfonate,(50 α).
CCKAR, CCKBR,
Pathogenic
Mechanistic CNR1,
genes:
genes: DRD1,
ANKK1,
ABCB1, DRD2,
BDNF,
AKT1, BDNF,DRD3,
GSK3B, LRRK2
CCK,
(1-methylethyl)-5′-(2-methylpropyl),monomethanesulfonate,(5′α).
IUPAC Name:Formula:
Molecular Ergotaman-3′-6′-18-trione,
C32 H40 BrN5 O5 CH4 SO 2-bromo-12′-hydroxy-2′- Mechanistic genes: ABCB1, AKT1, BDNF, CCK, CCKAR, CCKBR,
DRD4, DRD5,
CCKAR, GRIN2A, GRIN2B, GSK3B, HCRT,
CNR1,CCKBR, CNR1,DRD3,
DRD1, DRD2, DRD3,
3
Molecular
Molecular Formula:
Weight:C750.70
32H40BrN 5O5CH4SO3
(1-methylethyl)-5′-(2-methylpropyl),monomethanesulfonate,(5′α).
g/mol DRD1, DRD2, DRD4, DRD5, GRIN2A, GRIN2B,
HOMER1,
DRD4, LMO3,
DRD5, OPRM1
GRIN2A, GRIN2B, GSK3B, HCRT,
Molecular
Mechanism:
Molecular Weight:
Formula: 750.70
C32H40g/mol
Semisynthetic ergot alkaloid derivative and dopamine
BrN5O5CH4SO3
GSK3B, HCRT, HOMER1, LMO3, OPRM1
Int. J. Mol. Sci. 2017, 18, 551 receptor agonist which activates postsynaptic dopamine receptors in theMetabolic HOMER1, genes:
LMO3,
Metabolic genes:OPRM1 5 of 30
Mechanism:
Molecular Semisynthetic
Weight: 750.70 ergot alkaloid derivative and
g/mol
tuberoinfundibular (inhibiting pituitary prolactin secrection) and Substrate:
Metabolic genes:
Substrate: COMT,
COMT, CYP1A2,
CYP1A2, CY22B6,
CY22B6, CYP2C19, CYP2D6, CYP3A4
dopamine
Mechanism: receptor agonist
Semisynthetic which activates
ergot alkaloid postsynaptic
derivative
motorand
control). Causes CYP2C19,
(major), CYP2D6,
nigrostriatal
growth hormone
pathways (enhancing
secretion
coordinated
in acromegaly. Dysregulation of brain Substrate: COMT, CYP3A4
CYP3A5, DDC, MAOB,(major),
CYP1A2,
UGT1A1,CYP3A5,
CY22B6,
UGT1A9
dopamine
dopamine
transient receptors
receptor
increases ininthe
agonist tuberoinfundibular
which
growth activates
hormone (inhibiting
postsynaptic
secretion pituitary
in individuals with Inhibitor: CYP1A2 (weak), CYP3A4 (moderate)
serotonine activity may also occur. DDC, MAOB,
sustained CYP2C19,
UGT1A1,
CYP2D6, UGT1A9
genes:CYP3A4 SLC6A3CYP3A5,
SLC22A1,(major),
prolactin
normal
dopamine secrection)
growth hormone
receptors and
in thenigrostriatal
concentrations.pathways
tuberoinfundibular (enhancing
Paradoxically causes
(inhibiting pituitary Transporter
suppression agents;
of growth hormone Ergot-derivative dopamine
secretion in acromegaly. Dysregulation ofDDC, Inhibitor: CYP1A2
MAOB, genes:
Pleiotropic UGT1A1,ACE, APOECYP3A4 (moderate)
(weak),
UGT1A9
coordinated
prolactin motor
secrection) control).
and Causes
nigrostriatal transient
pathways increases in
(enhancing growth
receptor
brainagonists.
serotonine activity may also occur. Transporter
Inhibitor:genes: SLC22A1,
CYP1A2 (weak),SLC6A3
CYP3A4 (moderate)
hormone
Effect:secretion
coordinated motor in individuals
control). Causes with normalincreases
transient growth hormone
in growth
Name:
Antiparkinsonian
Cabergoline; 81409-90-7;
agents; Ergot-derivative
Cabergoline;
dopamine
Dostinex, Cabaser; Pleiotropic genes:
Transporter genes:ACE, APOESLC6A3
SLC22A1,
concentrations. Paradoxically causes sustained
hormone secretion in individuals with normal growth hormone
receptor agonists. suppression of
Cabergolinum; Cabaseril; Cabergolina. Pleiotropic genes: ACE, APOE
concentrations.
Name: Cabergoline;Paradoxically causes
81409-90-7; sustained
Cabergoline; suppression
Dostinex, Cabaser;of
IUPAC Name: Ergoline-8β-carboxamide, N-[3-
Cabergolinum; Cabaseril; Cabergolina. Pathogenic genes: BDNF, GSK3B
(dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl)
IUPAC Name: Ergoline-8β-carboxamide, Mechanistic genes: ADRA2A, ADRA2B, ADRA2C,
Molecular Formula: C26H37N5O2
N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl) Pathogenic genes: BDNF, GSK3B
AKT1, BDNF, CNR1, DRD1, DRD2, DRD3, DRD4,
Molecular
Formula: C26g/mol
H37 N5 O2 Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, AKT1, BDNF,
Molecular Weight: 451.60 g/mol DRD5,
CNR1,GSK3B,
DRD1,HTR1A, HTR1B,
DRD2, DRD3, HTR1D,
DRD4, HTR2A,
DRD5, GSK3B, HTR1A, HTR1B,
Mechanism: A long-acting dopamine receptor agonist. Has high
Mechanism: A long-acting dopamine receptor agonist. Has high bindingHTR2B, HTR1D,HTR2C,
HTR2A,HTR7
HTR2B, HTR2C, HTR7
binding affinity for dopamine D 2-receptors and lesser affinity for
affinity for dopamine D2 -receptors and lesser affinity for D1 , α1 - and Metabolic genes:
Metabolic genes:
D1, αα1-2 -adrenergic,
and α2-adrenergic,
and serotoninand serotonin
(5-HT1 and(5-HT and 5-HTReduces
5-HT2 1) receptors. 2) serum Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4
Substrate: COMT, CYP1A2, CYP2B6,
receptors.
prolactin Reduces serum prolactin
concentrations by inhibiting concentrations by inhibiting
release of prolactin from the anterior (minor), CYP3A5, DDC
CYP2C19, CYP2D6, CYP3A4 (minor), CYP3A5,
release of prolactin
pituitary from the
gland (agonist anterior
activity at Dpituitary
2 receptors). gland (agonist
Effect: Antiparkinsonian agents; Ergot-derivative dopamine DDC
activity at D 2 receptors).
receptor agonists.
Effect: Antiparkinsonian agents; Ergot-derivative dopamine
receptor agonists.
Name: Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine;
Dipergon; Lysenyl; Lisurida.
IUPAC Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-
1,1-diethylurea
DRD1, DRD2, DRD3, DRD4, DRD5, HTR1A,
Molecular Formula: C20H26N4O
HTR1B, HTR1D, HTR2A, HTR2B, HTR2C
Metabolic genes:
Mechanism: Displays dopaminergic, and consequently
Substrate: COMT, CYP1A2, CY22B6,
prolacting-reducing properties. Active substance lisuride has
CYP2C19, CYP2D6 (major), CYP3A4 (major),
pronounced affinity for dopamine receptors in striatum and
CYP3A5, DDC, UGT1A1, UGT1A9
pituitary.
IUPAC Name: Ergoline-8β-carboxamide, N-[3-
Pathogenic genes: BDNF, GSK3B
(dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl)
Molecular Formula: C26H37N5O2
AKT1, BDNF, CNR1, DRD1, DRD2, DRD3, DRD4,
DRD5, GSK3B, HTR1A, HTR1B, HTR1D, HTR2A,
Mechanism: A long-acting dopamine receptor agonist. Has high
HTR2B, HTR2C, HTR7
binding affinity for dopamine D2-receptors and lesser affinity for
Int. J. Mol. Sci. 2017, 18, 551 Metabolic genes: 5 of 28
D1, α1- and α2-adrenergic, and serotonin (5-HT1 and 5-HT2)
Substrate: COMT, CYP1A2, CYP2B6,
receptors. Reduces serum prolactin concentrations by inhibiting
CYP2C19, CYP2D6, CYP3A4 (minor), CYP3A5,
release of prolactin from the anterior pituitary gland (agonist
DDC
activity at D2 receptors). Table 1. Cont.
receptor agonists. Dopaminergic Agonists
Drug Name: Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine;
Dipergon; Lysenyl; Lisurida.
IUPAC Name:
Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-
Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine; Dipergon;
Lysenyl; Lisurida. Mechanistic genes: ADRA2A, ADRA2B, ADRA2C,
Int. J. Mol. Sci. 2017, 18, 551 1,1-diethylurea 6 of 30
IUPAC Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-1,1-diethylureaDRD1, DRD2, DRD3,
Mechanistic DRD4, DRD5,
genes: ADRA2A, HTR1A,
ADRA2B, ADRA2C, DRD1, DRD2,
Molecular Formula: C20CH2026H
N264O
Molecular Formula: N4 O HTR1B, HTR1D, HTR2A, HTR2B, HTR2C
DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, HTR2A, HTR2B,
Name: Pergolide;
Molecular
MolecularWeight: 66104-22-1;
338.45
Weight: 338.45 Pergolide; Permax; Pergolida;
g/mol
g/mol HTR2C
Metabolic genes:
Pergolidum.
Mechanism:
Mechanism: Displays
Displaysdopaminergic,
dopaminergic,and and consequently
consequently Metabolic genes:
Int. J. Mol. Sci. 2017, 18, 551 Substrate: COMT, CYP1A2, CY22B6, 6 of 30
IUPAC Name: Ergoline,8-[(methylthio)methyl]-6-
prolacting-reducing properties. Active substance lisuride has pronounced Substrate:
prolacting-reducing properties. Active substance lisuride has COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6 (major),
affinity for dopamine receptors in striatum and pituitary. CYP2C19,
CYP3A4CYP2D6
(major), CYP3A5, CYP3A4
(major), DDC, (major),
UGT1A1, UGT1A9
monomethenesulfonate
pronounced affinity for dopamine receptors in striatum and Mechanistic genes: ADRA1A, ADRA1B, ADRA1D,
Name: Pergolide;
Effect: 66104-22-1;
Antiparkinsonian Pergolide;
agents; Pergolida;receptor CYP3A5, DDC, UGT1A1, UGT1A9
Permax; dopamine
Ergot-derivative
Molecular
pituitary. Formula:
agonists. C19H26agents.
Antimigraine N2SCHMiscellaneous.
4O3S ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2,
Pergolidum.
Molecular Weight: 410.59 agents;
Effect: Antiparkinsonian g/mol Ergot-derivative dopamine DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D,
IUPAC Name:
Name: Ergoline,8-[(methylthio)methyl]-6-
Pergolide; 66104-22-1; Pergolide; Permax; Pergolida; Pergolidum.
Mechanism: A dopamin
receptor agonists. receptoragents.
Antimigraine agonist.Miscellaneous.
Relieves symptoms of HTR2A, HTR2B, HTR2C
IUPAC Name: Ergoline,8-[(methylthio)methyl]-6-monomethenesulfonateMechanistic genes: ADRA1A, ADRA1B, ADRA1D,
monomethenesulfonate
parkinsonism, presumably
Molecular Formula: C19 Hby Ndirectly
SCH4 Ostimulating
S postsynaptic Metabolic genes:
Molecular Formula: C19H26N2SCH4O3S 26 2 3 ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2,
dopamine receptors
Molecular Weight:in410.59
corpus striatum. Reduces serum prolactine
g/mol Substrate: COMT,
Mechanistic CYP1A2,ADRA1B,
genes: ADRA1A, CY22B6,ADRA1D, ADRA2A,
Molecular Weight: 410.59 g/mol DRD3, DRD4, DRD5, DRD1,
HTR1A, HTR1B, HTR1D,
concentrations
Mechanism: byAinhibiting
dopamin releaseagonist.
receptor of prolactin from
Relieves anteriorof
symptoms CYP2C19,
ADRA2B, CYP2D6,
ADRA2C, CYP3A4 (major),
DRD2, CYP3A5,
DRD3, DRD4, DRD5, HTR1A,
Mechanism: A dopamin
parkinsonism, presumably receptor
by agonist.
directly Relievespostsynaptic
stimulating symptomsdopamine
of HTR2A,
HTR1B,HTR2B,
HTR1D, HTR2C
HTR2A, HTR2B, HTR2C
pituitary gland. Causes transient increase in serum somatotropin DDC, UGT1A1, UGT1A9
parkinsonism,
receptors inpresumably
corpus striatum. by directly stimulating
Reduces serum prolactine concentrations byMetabolic
postsynaptic Metabolicgenes:
genes:
(growth hormone) concentrations and decreases in serum Transporter genes: SLC6A4
dopamine receptors
inhibiting release in prolactin
of corpus striatum.
from Reduces
anterior serum
pituitary prolactine
gland. Causes Substrate:
Substrate: COMT,
COMT, CYP1A2,
CYP1A2, CY22B6,
CY22B6, CYP2C19, CYP2D6, CYP3A4
luteinizing
transienthormone
increase concentrations.
in serum somatotropin (growth hormone) (major), CYP3A5, DDC, UGT1A1, UGT1A9
concentrations by and
inhibiting release of prolactin from anterior CYP2C19, CYP2D6, CYP3A4 (major), CYP3A5,
concentrations agents;inErgot-derivative
decreases serum luteinizingdopamine
hormone Transporter genes: SLC6A4
pituitary gland. Causes transient increase in serum somatotropin DDC, UGT1A1, UGT1A9
receptor agonists.
concentrations.
(growth hormone)
Effect: concentrations
Antiparkinsonian and decreases in
agents; Ergot-derivative serum
dopamine Transporter genes: SLC6A4
Name: Pramipexole; 104632-26-0; Pramipexole; Pramipexol; Pathogenic genes: ANKK1, BDNF, LRRK2
luteinizing
receptorhormone
agonists. concentrations.
Parmital; Mirapex; Mirapexin; Sifrol Mechanistic genes: ADRA2A, ADRA2B, ADRA2C,
IUPAC Name:
Name: 2,6-benzothiazolediamine,
Pramipexole; 104632-26-0; 4,5,6,7-tetrahydro-N
Pramipexole; Pramipexol; 6-
Parmital; CCK,Pathogenic
CCKAR, CCKBR, DRD1,BDNF,
genes: ANKK1, DRD2, DRD3,
LRRK2 Mechanistic genes:
receptor agonists.
Mirapex; Mirapexin; Sifrol
propyl-,(S) DRD4,
6 -propyl-,(S) DRD5,ADRA2B,
ADRA2A, GRIN2A,ADRA2C,
GRIN2B,CCK,HCRT,
CCKAR, CCKBR, DRD1, DRD2,
Name: Pramipexole; 104632-26-0; Pramipexole; Pramipexol;
IUPAC Name: 2,6-benzothiazolediamine, 4,5,6,7-tetrahydro-N Pathogenic genes: ANKK1, BDNF, LRRK2
Molecular Formula:
Molecular C10H
Formula: C1017N 3SN S
H17 HOMER1, HTR1A,
DRD3, DRD4, HTR1B,
DRD5, HTR1D,
GRIN2A, HTR2A,
GRIN2B, HCRT, HOMER1, HTR1A,
Parmital; Mirapex; Mirapexin; Sifrol
3
Mechanistic ADRA2A,
genes:HTR2A,
HTR1B, HTR1D, ADRA2B,
HTR2B, HTR2C,ADRA2C,
LMO3, OPRM1
Molecular Weight:
Molecular 211.33
Weight: 211.33g/mol
g/mol HTR2B, HTR2C, LMO3, OPRM1
IUPAC Name: 2,6-benzothiazolediamine, 4,5,6,7-tetrahydro-N 6- CCK, CCKAR,genes:
Metabolic CCKBR, DRD1, DRD2, DRD3,
Mechanism:
Mechanism: By binding
By binding to D
to2 Dsubfamily
2 subfamily dopamine
dopamine receptor, andto D3 , Metabolic
receptor, and genes:
Substrate: COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6, CYP3A4,
propyl-,(S) it is though that Pramipexole can stimulate dopamine DRD4, DRD5, GRIN2A, GRIN2B, HCRT,
to D3,and
andDD 4 receptors,
4 receptors, it is though that Pramipexole can Substrate:
CYP3A5, COMT,
DDC, MAOB, CYP1A2,
UGT1A1, CY22B6,
UGT1A9
Molecular
activityFormula:
on nervesC H17N3S and substantia nigra.
of10striatum HOMER1, HTR1A, HTR1B, HTR1D,
SLC6A3HTR2A,
stimulate
Effect:dopamine activityagents;
Antiparkinsonian on nerves of striatum anddopamine
Non-ergot-derivative CYP2C19, CYP2D6,
Transporter genes:CYP3A4,
SLC22A1, CYP3A5, DDC,
Molecular Weight: 211.33 g/mol HTR2B, HTR2C,
Pleiotropic LMO3,
genes: ACE,OPRM1
APOE
substantia
receptornigra.
agonists. MAOB, UGT1A1, UGT1A9
Mechanism: By binding to D2 subfamily dopamine receptor, and Metabolic genes:
Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Transporter genes: SLC22A1, SLC6A3
to D3, and D4 receptors, it is though that Pramipexole can Substrate: COMT, CYP1A2, CY22B6,
receptor agonists. Pleiotropic genes: ACE, APOE
stimulate dopamine activity on nerves of striatum and CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC,
substantia nigra. MAOB, UGT1A1, UGT1A9
Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Transporter genes: SLC22A1, SLC6A3
receptor agonists. Pleiotropic genes: ACE, APOE
Int. J. Mol. Sci. 2017, 18, 551 6 of 28
Int. J. Mol. Sci. 2017, 18, 551 7 of 30
Name: Ropinirole; 91374-21-9; Ropinirole; ReQuip; Ropinirol;

Ropinilorum; ReQuip CR Table 1. Cont.
Int. J. Mol. Sci. 2017, 18, 551 Pathogenic genes: ANKK1, BDNF, LRRK2 7 of 30
IUPAC Name: 2-H-Indol-2-one 4-[2-(dipropylamino)ethyl]-1,3-
dihydro-, monohydrochloride Dopaminergic Agonists
Name: Ropinirole; 91374-21-9; Ropinirole; ReQuip; Ropinirol; CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3,
Molecular Formula: C16H24N2O Properties
Drug Ropinilorum; ReQuip CR Pharmacogenetics
DRD4, DRD5, GRIN2A, GRIN2B, HCRT,
Molecular Weight: 296.84 g/mol Ropinirole; ReQuip; Ropinirol; Pathogenic genes: ANKK1, BDNF, LRRK2
IUPAC Name: 2-H-Indol-2-one 4-[2-(dipropylamino)ethyl]-1,3-
Name: Ropinirole; 91374-21-9; HOMER1, HTR1A, HTR1B, HTR1D, HTR2A,
Mechanism:
Ropinilorum; Has ReQuip
high relative
CR in vitro specificity and full intrinsic Mechanistic genes: ADRA2A, ADRA2B, ADRA2C,
dihydro-, monohydrochloride HTR2B, HTR2C, LMO3, OPRM1
activity
IUPACat DName:
2 and D 3 dopamine receptor
2-H-Indol-2-one subtypes, binding with
4-[2-(dipropylamino)ethyl]-1,3-dihydro-, CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3,
Molecular Formula: C 16H24N2O Metabolic genes:
Pathogenic genes: ANKK1, BDNF, LRRK2
higher affinity to D3 than to D2 and D4 receptor subtypes.
monohydrochloride DRD4, DRD5, GRIN2A, GRIN2B, HCRT,ADRA2C, CCK, CCKAR,
Molecular
Formula: C16g/mol
H24 N2 O
Mechanistic
Substrate: genes:
COMT, ADRA2A,
CYP1A2ADRA2B,
(major), CY22B6,
Although precise mechanism of action unknown, it is believed to HOMER1,
CCKBR, HTR1A, HTR1B,
DRD1, DRD2, HTR1D,
DRD3, DRD4,HTR2A,
DRD5, GRIN2A, GRIN2B,
Mechanism:
Molecular Has high296.84
Weight: relativeg/molin vitro specificity and full intrinsic CYP2C19, CYP2D6,HTR1A,
CYP3A4 (minor), CYP3A5,
be due to stimulation of postsynaptic dopamine D 2-type receptors HTR2B,
HCRT, HTR2C,
HOMER1, LMO3, OPRM1
HTR1B, HTR1D, HTR2A, HTR2B, HTR2C,
activity at D2 and D3 dopamine receptor subtypes, binding with
Mechanism: Has high relative in vitro specificity and full intrinsic activity
DDC, MAOB,
LMO3, UGT1A1, UGT1A9
OPRM1
within caudate
at D 2 and D3putamen
dopamineinreceptorbrain. subtypes,
Mechanism of with higher affinity toMetabolic genes:
binding
higher affinity to D3 than to D2 and D4 receptor subtypes. CYP1A2 (moderate), CYP2D6
Inhibitor:genes:
Metabolic
Ropinirole-induced
D3 than to D2 andpostural D4 receptor hypotension believedprecise
subtypes. Although to be due to
mechanism of Substrate: COMT, CYP1A2 (major), CY22B6,
Although
action precise
unknown, mechanism
it is believed of to
action unknown,
be due it is believed
to stimulation to
of postsynaptic
Substrate:
(moderate), COMT,
CYP3A4 CYP1A2
(moderate)(major), CY22B6, CYP2C19, CYP2D6,
D2-mediated blunting of noradrenergic response to standing and CYP2C19,
CYP3A4CYP2D6, CYP3A4DDC,
(minor), CYP3A5, (minor),
MAOB,CYP3A5,
UGT1A1, UGT1A9
be due to stimulation
dopamine D2 -type of postsynaptic
receptors dopamine
within caudate D2-type
putamen receptors
in brain. Transporter genes: SLC22A1, SLC6A3
subsequent decrease in peripheral vascular postural resistance. believed to be DDC, MAOB,CYP1A2
UGT1A1, UGT1A9
Inhibitor: (moderate), CYP2D6 (moderate), CYP3A4 (moderate)
within caudate putamen
Mechanism in brain. Mechanism
of Ropinirole-induced of
hypotension Pleiotropic genes: ACE, APOESLC6A3
Effect:
dueAntiparkinsonian
to D2 -mediated blunting agents;ofNon-ergot-derivative
noradrenergic response dopamine
to standing and Inhibitor: CYP1A2
Transporter genes: (moderate),
SLC22A1, CYP2D6
Ropinirole-induced postural hypotension believed to be due to Pleiotropic genes: ACE, APOE
receptor agonists.
subsequent decrease in peripheral vascular resistance. (moderate), CYP3A4 (moderate)
D2-mediated blunting of noradrenergic response to standing and
Effect: Antiparkinsonian agents; Non-ergot-derivative
Name: Rotigotine; 99755-59-6; Rotigotine; Rotigotina; Neupro
dopamine Transporter genes: SLC22A1, SLC6A3
subsequent
receptordecrease
agonists. in peripheral vascular resistance.
IUPAC Name: 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2- Pleiotropic genes: ACE, APOE
Name: agents;Rotigotine;
Rotigotine; 99755-59-6; Non-ergot-derivative
Rotigotina; Neuprodopamine
thienyl)ethyl]amino]-6S
receptor
IUPAC agonists.
Name: 1-Naphthalenol,
Molecular Formula: C19H25NOs Pathogenic genes: ANKK1, BDNF, LRRK2
Name: Rotigotine; 99755-59-6; Rotigotine; Rotigotina; Neupro
5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-6S
Molecular
Formula: C19g/mol
H25 NOs Mechanistic genes:CCK,
Pathogenicgenes: CCKAR,
ANKK1, BDNF,CCKBR,
LRRK2 DRD1,
H3C
IUPAC Name: 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-
Mechanism:
MolecularAWeight:non-ergot315.47 dopamine
g/mol receptor agonist with DRD2, DRD3, DRD4,
Mechanistic DRD5,
genes: CCK, GRIN2A,
CCKAR, GRIN2B,
CCKBR, DRD1, DRD2, DRD3,
thienyl)ethyl]amino]-6S
Mechanism: A non-ergot dopamine receptor agonist with specificity for DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1
specificity for D3-, D2-, and D1-dopamine receptors. Although HCRT, HOMER1, LMO3, OPRM1
Molecular
D3 -, D2Formula: C19H25NOs
-, and D1 -dopamine receptors. Although precise mechanism of Pathogenic genes:ANKK1, BDNF, LRRK2
Metabolicgenes:
precise mechanism of action unknown of Rotigotine, it is believed Metabolic genes:
COMT,CCK,
Molecular
action Weight: 315.47
unknown g/mol it is believed to be due to stimulation of Mechanistic
of Rotigotine, Substrate: genes: MAOB CCKAR, CCKBR, DRD1,
to bepostsynaptic
due to stimulation ofDpostsynaptic dopamine D2substantia Substrate: COMT,
-type autonigra in Transporter MAOBSLC6A3
H3C
Mechanism: dopamine
A non-ergot 2 -type auto
dopamine receptors
receptor within
agonist with DRD2, DRD3, genes:DRD4,SLC22A1,
DRD5, GRIN2A, GRIN2B,
receptors within substantia nigra in brain, leading to improved
brain, leading to improved dopaminergic transmission in motor areas inTransporter genes: SLC22A1,
Pleiotropic genes: ACE, APOE SLC6A3
specificity for D3-,notably
D2-, and D1-dopamine receptors. Although HCRT, HOMER1, LMO3, OPRM1
dopaminergic transmission in motor areas in basal ganglia,
basal ganglia, caudate nucleus/putamen regions. Pleiotropic genes: ACE, APOE
precise mechanism
Effect: of actionagents;
Antiparkinsonian unknown of Rotigotine, itdopamine
Non-ergot-derivative is believed Metabolic genes:
notably caudate nucleus/putamen regions.
to bereceptor
due to stimulation
agonists. of postsynaptic dopamine D2-type auto Substrate: COMT, MAOB
Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine
receptors within substantia nigra in brain, leading to improved Transporter genes: SLC22A1, SLC6A3
receptor agonists.
dopaminergic transmission in motor areas in basal ganglia, Pleiotropic genes: ACE, APOE
Monoamine Oxidase B (MOB) Inhibitors
notably caudate nucleus/putamen regions.
Drug Effect: Antiparkinsonian agents; Properties
Non-ergot-derivative dopamine Pharmacogenetics
receptor agonists.
Monoamine Oxidase B (MOB) Inhibitors
Int. J.18,
Int. J. Mol. Sci. 2017, Mol.551
Sci. 2017, 18, 551 8 of 30 7 of 28
Pathogenic genes: ANKK1, BDNF, LRRK2

Name: Selegiline; 14611-51-9; Selegiline; Selegilina; L-Deprenalin;
Mechanistic genes: CCK, CCKAR, CCKBR, DRD1,
Emsam; Jumex; Eldepryl; Carbex Table 1. Cont.
Int. J. Mol. Sci. 2017, 18, 551 DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, 8 of 30
IUPAC Name: Benzeneethanamine,N,α-dimethyl-N-2-propynyl-
HCRT, HOMER1, LMO3, OPRM1
,hydrochloride,(R) Monoamine Oxidase B (MOB) Inhibitors Pathogenic genes: ANKK1, BDNF, LRRK2
Name: Selegiline; 14611-51-9; Selegiline; Selegilina; L-Deprenalin; Metabolic genes:
Molecular Formula: C31H17NHCl Properties Mechanistic genes: CCK, CCKAR, CCKBR,(minor),
DRD1,
Drug
Emsam; Jumex; Eldepryl; Substrate: COMT, CYP1A1, CYP1A2
Pharmacogenetics
Molecular Weight: 223.74 Carbex
g/mol DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B,
IUPACName:
Name:Selegiline; 14611-51-9; Selegiline; Selegilina;
Benzeneethanamine,N,α-dimethyl-N-2-propynyl- L-Deprenalin; Emsam; CYP1B1, CYP2A6 (minor), CYP2B6 (major),
Mechanism: Potent, irreversible inhibitor of the monoamine HCRT, HOMER1, LMO3, OPRM1
Jumex; Eldepryl;
,hydrochloride,(R)
Carbex CYP2C8 (minor),
Pathogenic CYP2C19
genes: ANKK1, BDNF, CYP2D6
(major), LRRK2
oxidase
IUPAC Name:Plasma concentrations achieved via
(MAO). Metabolic genes:
Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3,
Molecular Formula: C31dosage
H17NHCl (minor), CYP2E1 (minor), CYP3A4 (minor),
administration of oral forms in recommended doses confer
Benzeneethanamine,N,α-dimethyl-N-2-propynyl-,hydrochloride,(R) DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1
Substrate: COMT, CYP1A1, CYP1A2 (minor),
Molecular Weight: 223.74 g/mol CYP3A5, CYP19A1,
genes: DDC, MAOA, MAOB,
selective inhibition
Molecular of the
Formula: C31MAO
H17 NHCltype B, which plays a major role in CYP1B1, Metabolic
CYP2A6 (minor), CYP2B6 (major),
Mechanism:
Molecular Potent,
Weight:irreversible
223.74 g/mol inhibitor of the monoamine UGT1A1, UGT1A9
Substrate: COMT, CYP1A1, CYP1A2 (minor), CYP1B1, CYP2A6
metabolism of dopamine. Selegiline may also increase CYP2C8 (minor), CYP2C19 (major), CYP2D6
Mechanism: Potent, irreversible inhibitor of the monoamine oxidase
oxidase (MAO). Plasma concentrations achieved via Inhibitor:
(minor), CYP1A2
CYP2B6 (weak),
(major), CYP2C8CYP2A6 (weak),
(minor), CYP2C19 (major), CYP2D6
dopaminergic
(MAO). Plasma activity by interfering
concentrations withvia
achieved dopamine reuptake
administration (minor),
of oral dosage CYP2E1
(minor), CYP2E1 (minor),CYP3A4
(minor), CYP3A4 (minor),
(minor), CYP3A5, CYP19A1, DDC,
administration of oral dosage forms CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (weak),
at synapse.
forms in recommended doses conferinselective
recommended
inhibitiondoses
of theconfer
MAO type MAOA,
CYP3A5, MAOB, UGT1A1,
CYP19A1, UGT1A9MAOB,
DDC,(weak),
MAOA,
selective inhibition of the MAO type B, which plays a major role in CYP2E1 (weak), CYP3A4 MAOB
Effect: Antidepressants. Monoamine oxidase inhibitors.
B, which plays a major role in metabolism of dopamine. Selegiline may Inhibitor:
UGT1A1,
CYP1A2 (weak), CYP2A6 (weak), CYP2C9 (weak), CYP2C19
metabolism of dopamine.
also increase dopaminergic Selegiline
activitymay also increase
by interfering with dopamine (weak), UGT1A9
Transporter CYP2D6 SLC22A1,
genes:(weak), CYP2E1 SLC6A3
(weak), CYP3A4 (weak), MAOB
Antiparkinsonian agents. Monoamine oxidase B inhibitors. Inhibitor: CYP1A2 (weak), CYP2A6 (weak),
reuptake at synapse.
dopaminergic activity by interfering with dopamine reuptake Pleiotropic genes:
Transporter ACE,
genes: APOESLC6A3
SLC22A1,
Name:Effect: Antidepressants.
Rasagiline; 136236-51-6;Monoamine
Azilet; oxidase
Elbrux; inhibitors. Antiparkinsonian
Rasagilina; Raxac. CYP2C9 (weak),
Pleiotropic CYP2C19
genes: (weak), CYP2D6 (weak),
ACE, APOE
at synapse.
agents. Monoamine oxidase B inhibitors.
IUPACAntidepressants.
Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-,(R)-, CYP2E1 (weak), CYP3A4 (weak), MAOB
Effect: Monoamine oxidase inhibitors.
Name: Rasagiline; 136236-51-6; Azilet; Elbrux; Rasagilina; Raxac.
methanesulfonate Transporter genes:ANKK1,
Pathogenic genes: SLC22A1, BDNF,
SLC6A3LRRK2, PARK2
Antiparkinsonian agents. Monoamine oxidase B inhibitors. Mechanisticgenes: BLC2,
genes:ACE, CCK, CCKAR, CCKBR,
IUPAC Name: 1H-Inden-1-amine,
Molecular Formula: C12H13NCH4O3S
2,3-dihydro-N-2-propynyl-,(R)-, Pleiotropic APOE
Name:
methanesulfonate
Rasagiline; 136236-51-6; Azilet; Elbrux; Rasagilina; Raxac. DRD1, DRD2, DRD3,
Mechanistic DRD4,
genes: BLC2, DRD5,
CCK, CCKAR,GRIN2A,
CCKBR, DRD1, DRD2,
Molecular Weight:
Molecular 267.34
Formula: C12g/mol
H13 NCH 4 O3 S
IUPAC Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-,(R)-, GRIN2B,
DRD3,HCRT,
DRD4, HOMER1,
DRD5, GRIN2A, LMO3, OPRM1
GRIN2B, HCRT, HOMER1, LMO3,
Mechanism:
Molecular Potent,
Weight:irreversible
267.34 g/mol inhibitor of the MAO type B, Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2
methanesulfonate Metabolic
OPRM1genes:
which plays a major role in catabolism of dopamine. Inhibition of
Mechanism: Potent, irreversible inhibitor of the MAO type B, which plays
Mechanistic genes: BLC2, CCK, CCKAR, CCKBR,
Metabolicgenes:
Molecular
a majorFormula: Substrate: COMT, CYP1A2 (major), CYP2B6,
depletion C in12H 13NCH 4O3S of brain reduces
role in catabolism of dopamine. Inhibition of dopamine depletion
dopamine striatal region Substrate: COMT, CYP1A2 (major), CYP2B6, CYP2C19, CYP2D6,
DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A,
in striatal region of brain reduces symptomatic motor deficits of
Molecular Weight: 267.34 g/mol CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC,
symptomatic
Parkinson’s motor deficits
Disease. ThereofisParkinson’s Disease.
also experimental There
evidence of is also
Rasagiline
CYP3A4,
GRIN2B,
CYP3A5,
HCRT,
DDC,
HOMER1,
MAOB, UGT1A1,
LMO3, OPRM1
UGT1A9
Mechanism: Potent, irreversible inhibitor of theantiapoptotic),
MAO type B,which may MAOB, UGT1A1,
Inhibitor: MAOB UGT1A9
experimental
conferring evidence of Rasagiline
neuroprotective effects conferring
(antioxidant, neuroprotective Metabolic genes:
which plays a major role in catabolism of dopamine. Inhibitor:
Transporter MAOB
genes: SLC22A1, SLC6A3
effects (antioxidant,
delay onset antiapoptotic),
of symptoms which
and progression may delay Inhibition
of neuronal onset of of
deterioration.
Substrate:
Pleiotropic COMT,
genes: CYP1A2
ACE, APOE (major), CYP2B6,
dopamine Transporter genes: SLC22A1, SLC6A3
symptoms depletion in striatal region of deterioration.
brain reduces
Effect: Antidepressants. Monoamine oxidase inhibitors. Antiparkinsonian
and progression of neuronal CYP2C19,
Agents. Monoamine oxidase B inhibitors.
symptomatic motor deficits of Parkinson’s Disease. There is also Pleiotropic genes: ACE, APOECYP3A5, DDC,
CYP2D6, CYP3A4,
Effect: Antidepressants. Monoamine oxidase inhibitors. MAOB, UGT1A1, UGT1A9
experimental
Antiparkinsonian evidence
Agents. of Rasagiline
Monoamine conferring
oxidase B neuroprotective
inhibitors. Inhibitor: MAOB
effects (antioxidant, antiapoptotic), which may delay(COMT)
Catecol-O-methyltransferase onset ofInhibitors
Transporter genes: SLC22A1, SLC6A3
Drug symptoms and progression of neuronal deterioration.
Pleiotropic genes: ACE, APOE
Effect: Antidepressants. Monoamine oxidase inhibitors.
Antiparkinsonian Agents. Monoamine oxidase B inhibitors.
Catecol-O-methyltransferase (COMT) Inhibitors
Int. J. Mol. Sci. 2017, 18, 551 9 of 30
Int. J. Mol. Sci. 2017, 18, 551 8 of 28
Name: Entacapone; 130929-57-6; Comtan; Comtess; Entacapona. Mechanistic genes: CCK, CCKAR, CCKBR, DRD1,
Int. J. Mol. Sci. 2017, 18, 551 IUPAC Name: E-α-cyano-N,N-diethyl-3,4-dihydroxy-5- Table 1. Cont. DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, 9 of 30
CH 3
nitrocinnamamida HCRT, HOMER1, LMO3, OPRM1
Molecular Formula: C14H15N3OCatecol-O-methyltransferase
5 Metabolic
(COMT) Inhibitors genes: ANKK1, BDNF, LRRK2, PARK2
Pathogenicgenes:
CH
Name: Entacapone;
Molecular 130929-57-6;
Weight: 305.29 g/mol Comtan;
PropertiesComtess; Entacapona. Mechanistic
Substrate:genes:
COMT,CCK, CCKAR,
CYP1A2, CCKBR, DRD1,
CYP2B6,
3
Drug Pharmacogenetics
IUPAC
Mechanism:Name: A E-α-cyano-N,N-diethyl-3,4-dihydroxy-5-
selective and selective inhibitor of COMT. When DRD2, DRD3,
CYP2C19, DRD4,
CYP2D6, DRD5, GRIN2A,
CYP3A4, CYP3A5, GRIN2B,
DDC,
CH 3
nitrocinnamamida
entacapona is taken with
Name: Entacapone; levodopa,Comtan;
130929-57-6; the pharmacokinetics are
Comtess; Entacapona. HCRT,
MAOB, HOMER1,
UGT1A1,
Mechanistic LMO3,
genes: CCK,OPRM1
UGT1A3, UGT1A4,
CCKAR, UGT1A6,
CCKBR, DRD1, DRD2, DRD3,
CH
Molecular
altered,
IUPAC Formula:
resulting
Name: in C14H15sustained
more N3O5 levodopa serum levels
E-α-cyano-N,N-diethyl-3,4-dihydroxy-5-nitrocinnamamida Metabolic
UGT1A9, genes: GRIN2A,
DRD4,UGT2B7,
DRD5, UGT2B15GRIN2B, HCRT, HOMER1, LMO3, OPRM1
Molecular
compared Weight:
to levodopa305.29C14g/mol Substrate: COMT, CYP1A2
COMT,
Inhibitor:genes: CYP1A2,(weak),
CYP2B6,CYP2A6
3
Molecular Formula: H15 N3 O5 Metabolic
Molecular Weight: 305.29 g/mol Substrate:
CYP2C19, COMT,CYP3A4,
CYP2D6, CYP1A2, CYP2B6,
CYP3A5, CYP2C19, CYP2D6, CYP3A4,
Mechanism:
taken alone. A selective and selective inhibitor of COMT. When (weak), CYP2C9 (weak), CYP2C19 (weak),DDC,
CYP2D6
Mechanism: A selective and selective inhibitor of COMT. When CYP3A5, DDC, MAOB, UGT1A1, UGT1A3, UGT1A4, UGT1A6,
entacapona
Effect: is taken
Antiparkinsonian
entacapona with
is taken levodopa,
agents.
with the
thepharmacokinetics
Catechol-O-methyltransferase
levodopa, pharmacokinetics are MAOB,
arealtered, (weak), UGT1A1,
CYP2E1
UGT1A9, UGT1A3,
(weak),
UGT2B7, CYP3A4
UGT2B15 UGT1A4,
(weak)UGT1A6,
altered,
inhibitors.resulting
resulting in more
in more sustained
sustained levodopa levodopa serum
serum levels levels to levodopa
compared UGT1A9,
Transporter UGT2B7,
Inhibitor: genes: UGT2B15
COMT,SLC22A1, SLC6A3
CYP1A2 (weak), CYP2A6 (weak), CYP2C9 (weak),
compared to levodopa
taken alone. Inhibitor:
Pleiotropic
CYP2C19 COMT,
genes: ACE,
(weak), CYP1A2
CYP2D6ACHE, (weak),
APOE
(weak), CYP2A6
CYP2E1 (weak), CYP3A4 (weak)
takenEffect:
Name: alone. Antiparkinsonian agents. Catechol-O-methyltransferase inhibitors.
Tolcapone; 134308-13-7; Tolcapona; Tasmar. (weak), CYP2C9
Transporter
Pathogenic (weak),
genes:
genes: ANKK1,CYP2C19
SLC22A1,
BDNF, (weak),
SLC6A3
LRRK2,CYP2D6
PARK2
Pleiotropic genes: ACE, ACHE, APOE
IUPAC Name: Methanone, agents. Catechol-O-methyltransferase
(3,4-hydroxy-5-nitrophenyl)(4- (weak), CYP2E1
Mechanistic (weak),
genes: AKT1,CYP3A4
CCK, (weak)
CCKAR, CCKBR,
inhibitors.
methylphenyl)
Name: Tolcapone; 134308-13-7; Tolcapona; Tasmar. Transporter
CNR1, DRD1,
Pathogenic genes:
DRD2,
genes:SLC22A1,
ANKK1, SLC6A3
DRD3,BDNF,
DRD4, DRD5,PARK2
LRRK2, GPT,
IUPAC Name: Methanone, (3,4-hydroxy-5-nitrophenyl)(4-methylphenyl)Pleiotropic
Molecular Formula: C14H11NO5 genes:
Mechanistic
GRIN2A, GRIN2B, ACE,
genes:
GSK3B,ACHE,
AKT1, CCK,APOE
HCRT,
CCKAR, CCKBR, CNR1, DRD1,
HOMER1,
Molecular Formula: C14 H11 NO5 DRD2, DRD3, DRD4, DRD5, GPT, GRIN2A, GRIN2B, GSK3B, HCRT,
Name:
Molecular Tolcapone;
Weight:
Molecular 134308-13-7;
273.24
Weight: g/mol
273.24 g/molTolcapona; Tasmar. Pathogenic
LMO3, OPRM1
HOMER1, genes:
LMO3, ANKK1,
OPRM1BDNF, LRRK2, PARK2
IUPAC
Mechanism:Name:
Mechanism: A Methanone,
selective
A selectiveand (3,4-hydroxy-5-nitrophenyl)(4-
selective
and selectiveinhibitor of (COMT.
inhibitor of (COMT.InInthethe
presenceMechanistic
Metabolic genes: AKT1, CCK, CCKAR, CCKBR,
genes:
genes:
Metabolic
methylphenyl)
presence of a decarboxylase
of a decarboxylase inhibitor
inhibitor (e.g., carbidopa),
(e.g., carbidopa), COMT
COMT is the majoris CNR1, DRD1,COMT,
Substrate:
Substrate: DRD2,
COMT, DRD3,
CYP1A2,
CYP1A2, DRD4,
CYP2B6, DRD5,
CYP2B6,
CYP2C9, GPT,
CYP2C9,
CYP2C19, CYP2D6,
Molecular Formula:
degradation
the major pathway
degradation levodopa. Inhibition of COMT leads to more GRIN2A,
C14pathway
Hfor
11NO5 for levodopa. Inhibition of COMT
CYP3A4,
CYP2C19, GRIN2B,
CYP3A5,
CYP2D6, GSK3B, HCRT,
DDC, MAOB,
CYP3A4, CYP3A5, HOMER1,
UGT1A1,
DDC,UGT1A3, UGT1A4,
sustained plasma levels of levodopa and enhanced central dopaminergic UGT1A6, UGT1A9, UGT2B7, UGT2B15
Molecular Weight: 273.24plasma
g/mol levels of levodopa and enhanced LMO3,
MAOB, OPRM1
UGT1A1, UGT1A3, UGT1A4,
leadsactivity.
to more sustained Transporter genes: SLC22A1, SLC6A3 UGT1A6,
CH 3
Mechanism:
central A selective
dopaminergic
Effect: andagents.
selective
activity.
Antiparkinsonian inhibitor of (COMT. In the
Catechol-O-methyltransferase Metabolic
UGT1A9,
inhibitors. genes:
UGT2B7,
Pleiotropic genes:UGT2B15
ACE, APOE
presence
Effect: of a decarboxylase
Antiparkinsonian inhibitor
agents. (e.g., carbidopa), COMT is
Catechol-O-methyltransferase Substrate:
Transporter COMT,
genes: CYP1A2,
SLC22A1, CYP2B6, CYP2C9,
SLC6A3
ABCB1: ATP binding cassette subfamily B member 1; ACE: Angiotensin I converting enzyme; ACHE: Acetylcholinesterase;
CYP2C19, CYP2D6, ADCY7:
CYP3A4, Adenylate cyclase 7; ADRA1A: Adrenoceptor α1A;
the major degradation
inhibitors. pathway for levodopa. Inhibition of COMT Pleiotropic genes: ACE, APOECYP3A5, DDC,
ADRA1B: Adrenoceptor α1B; ADRA1D: Adrenoceptor α1D; ADRA2A: Adrenoceptor α2A; ADRA2B: Adrenoceptor α2B; ADRA2C: Adrenoceptor α2C; AKT1: v-Akt murine thymoma
ABCB1: ATP binding cassette leads to more
subfamily sustained plasma levels Iofconverting
levodopaenzyme;
and enhanced MAOB, UGT1A1, UGT1A3, UGT1A4, UGT1A6,
viral oncogene homolog 1; ANKK1: Ankyrin repeat Bandmember
kinase 1; ACE:
domainAngiotensin
containing ACHE: Acetylcholinesterase;
1; APOE: Apolipoprotein ADCY7:
E; BDNF: Brain-derived Adenylate cyclase
neurotrophic 7; ADRA1A:
factor; BLC2: B-cell chronic lymphocytic
central dopaminergicα1B; activity. UGT1A9, UGT2B7, UGT2B15
CH
Adrenoceptor α1A; ADRA1B: Adrenoceptor ADRA1D: Adrenoceptor α1D; ADRA2A: Adrenoceptor α2A; ADRA2B: Adrenoceptor α2B; ADRA2C:
3
leukemia (CLL)/lymphoma 2; CALY: Calcyon neuron specific vesicular protein; CCK: Cholecystokinin, CCKAR: Cholecystokinin A receptor; CCKBR: Cholecystokinin B receptor;
CCR5: C–C motif Adrenoceptor
chemokineα2C; receptor Effect:
AKT1: 5v-Akt Antiparkinsonian
murine thymoma viral
(gene/pseudogene); CHAT: agents.
oncogene
CholineCatechol-O-methyltransferase
homolog 1; ANKK1: AnkyrinCNR1:
O-acetyltransferase; repeat and Transporter
kinase domain
Cannabinoid genes: SLC22A1,
containing
receptor SLC6A3
1; APOE:
1 (brain); Apolipoprotein
COMT: E;
Catechol-O-methyltransferase; CREB1:
cAMP responsive BDNF: Brain-derived
element inhibitors.
bindingneurotrophic
protein 1; factor;
CXCR4: BLC2: B-cell chronic
C–X–C lymphocytic receptor
motif chemokine leukemia (CLL)/lymphoma 2; Pleiotropic
4; CYP1A1: CytochromeCALY: Calcyongenes:
P450 ACE,
neuron
family 1APOE
specific vesicular
subfamily Aprotein;
member CCK:1; CYP1A2: Cytochrome P450
Cholecystokinin,
ABCB1:
family 1 subfamily A member CCKAR:
ATP binding
2; CYP1B1:Cholecystokinin
cassette subfamily
Cytochrome A receptor;
B member CCKBR:
P4501; family
ACE: Cholecystokinin
Angiotensin
1 subfamily B receptor;
I converting
B member enzyme; CCR5: C–C
ACHE:
1; CYP2A6: motif chemokine
Acetylcholinesterase;
Cytochrome receptor
P450ADCY7: 25 subfamily
(gene/pseudogene);
familyAdenylate cyclase
A 7; CHAT:
ADRA1A:
member 6; CYP2B6: Cytochrome P450
Choline
family 2 subfamily O-acetyltransferase;
Adrenoceptor
B member α1A; ADRA1B:
6; CYP2C19: CNR1: Cannabinoid
Adrenoceptor
Cytochrome receptor
α1B;
P450 1 (brain);
ADRA1D:
family COMT: Catechol-O-methyltransferase;
2 Adrenoceptor
subfamily Cα1D; ADRA2A:
member Adrenoceptor
19; CYP2C9: CREB1: cAMP
α2A;
Cytochrome responsive
ADRA2B:
P450 element
Adrenoceptor
family binding protein
α2B; ADRA2C:
2 subfamily C member1; 9; CYP2D6: Cytochrome
CXCR4: C–X–C
Adrenoceptor
P450 family 2 subfamily motif
α2C;
D member chemokine
AKT1:
6; v-Akt receptor
murine
CYP2E1: 4; CYP1A1:
thymoma
Cytochrome Cytochrome
viral
P450oncogene P450
familyhomolog family 1 subfamily
1; ANKK1:
2 subfamily A member
Ankyrin
E member 1;repeat1;and
CYP3A4: CYP1A2:
kinase Cytochrome P450
domain containing
Cytochrome P450 family
family 31 subfamily
1; APOE: subfamily AAmember
Apolipoprotein E;
member 4; CYP3A5: Cytochrome
2; CYP1B1:
BDNF:
P450 family 3 subfamily ACytochrome
Brain-derived
member 5;P450 family
neurotrophic
CYP19A1: 1 Cytochrome
subfamily
factor; B member
BLC2: B-cell chronic
P450 1; lymphocytic
CYP2A6:
family Cytochrome P450 family1;
leukemiaA(CLL)/lymphoma
19 subfamily member 2 subfamily
DBH:2; CALY:A Calcyon
memberβ-hydroxylase;
Dopamine 6; CYP2B6:
neuron specificCytochrome
vesicular P450 family
protein;
DDC: DOPA CCK:2
decarboxylase; DRD1: Dopamine
Cholecystokinin,
receptor D1; DRD2: DopamineCCKAR:receptorCholecystokinin
D2; DRD3: DopamineA receptor;receptor
CCKBR: Cholecystokinin
D3; DRD4: DopamineB receptor; CCR5: C–C
receptor D4; motif
DRD5:chemokine
Dopaminereceptor 5 (gene/pseudogene);
receptor CHAT:
D5; G6PD: Glucose-6-phosphate dehydrogenase;
Choline O-acetyltransferase;
GPT: Glutamic-pyruvate CNR1: Cannabinoid
transaminase (alanine receptor 1 (brain);
aminotransferase); GRIN2A: COMT: Catechol-O-methyltransferase;
Glutamate ionotropic receptor CREB1: cAMP responsive
N-methyl- D -aspartate element
(NMDA) binding protein
type 1;
subunit 2A; GRIN2B: Glutamate
CXCR4:
ionotropic receptor C–X–Ctype
NMDA motifsubunit
chemokine 2B;receptor
GRIN3A: 4; CYP1A1:
GlutamateCytochrome P450 family
ionotropic 1 subfamily
receptor NMDAAtype member 1; CYP1A2:
subunit Cytochrome
3A; GSK3B: P450 family
Glycogen 1 subfamily
synthase kinaseA member
3 beta; HCRT: Hypocretin (orexin)
2; CYP1B1:HOMER1:
neuropeptide precursor; CytochromeHomer
P450 family 1 subfamily
scaffolding protein 1; HRH1:
B member 1; CYP2A6: Cytochrome
Histamine P450
receptor H1; HTR1A:
family 2 subfamily A member 6; CYP2B6:
5-Hydroxytryptamine receptor 1A; HTR1B:
Cytochrome P450 family 2
5-Hydroxytryptamine receptor 1B;
HTR1D: 5-Hydroxytryptamine receptor 1D; HTR2A: 5-Hydroxytryptamine receptor 2A; HTR2B: 5-Hydroxytryptamine receptor 2B; HTR2C: 5-Hydroxytryptamine receptor 2C; HTR7:
5-Hydroxytryptamine receptor 7; LMO3: LIM domain only 3; LRRK2: Leucine-rich repeat kinase 2; MAOA: Monoamine oxidase A; MAOB: Monoamine oxidase B; OPRM1: Opioid
receptor mu 1; PAH: phenylalanine hydroxylase; PARK2: Parkin RBR E3 ubiquitin protein ligase; SLC22A1: Solute carrier family 22 member 1; SLC6A3: Solute carrier family 6 member
3; SLC6A4: Solute carrier family 6 member 4; SST: Somatostatin; TH: Tyrosine hydroxylase; TSPO: Translocator protein; UGT1A1: UDP glucuronosyltransferase family 1 member A1;
UGT1A3: UDP glucuronosyltransferase family 1 member A3; UGT1A4: UDP glucuronosyltransferase family 1 member A4; UGT1A6: UDP glucuronosyltransferase family 1 member A6;
UGT1A9: UDP glucuronosyltransferase family 1 member A9; UGT2B7: UDP glucuronosyltransferase family 2 member B7; UGT2B15: UDP glucuronosyltransferase family 2 member B15.
(Source: R. Cacabelos et al., [17,19]). IUPAC: International Union of Pure and Applied Chemistry.
Int. J. Mol. Sci. 2017, 18, 551 9 of 28
2. Pathogenic Mechanisms
As in other prevalent age-related neurodegenerative disorders, it is plausible that the confluence
of genomic vulnerability with diverse environmental factors may be responsible for the growing impact
of PD in our society. Parkinson’s disease-related neurodegeneration is likely to occur several decades
before the onset of the motor symptoms [20]. Associated with different potentially pathogenic risk
factors (toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, genomic defects),
PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra
pars compacta and Lewy body deposition, with widespread involvement of other CNS structures and
peripheral tissues [21–23]. Parkinson’s disease is a form of multisystemic α-synucleinopathy with Lewy
bodies deposited in the midbrain. Descriptive phenomena to explain in part this neuropathological
phenotype include the following: (i) genomic factors; (ii) epigenetic changes; (iii) toxic factors;
(iv) oxidative stress anomalies; (v) neuroimmune/neuroinflammatory reactions; (vi) hypoxic-ischemic
conditions; (vii) metabolic deficiencies; and (viii) ubiquitin–proteasome system dysfunction [19,23–29];
all these conditions leading to protein misfolding and aggregation and premature neuronal death.
Recent evidence also suggests that PD might be a prion-like disease [30]. Telomere shortening as
a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of
aging which might also contribute to PD pathology [31].
Mutations in a series of primary genes are known to cause autosomal dominant and recessive
forms of PD [28–38]. Mutations in some genes—e.g., α-Synuclein (SNCA), Parkin 2 (PARK2),
PTEN-induced putative kinase 1 (PINK1), PARK7, Leucine-rich repeat kinase 2 (LRRK2), Bone narrow
stromal cell antigen 1 (BST1), Microtubule-associated protein tau (MAPT)—might be causative in
familial forms of PD whereas diverse genetic defects in other loci might represent susceptibility
loci associated with sporadic PD without family history [28,34–39]. Mendelian variants with high
penetrance (e.g., SNCA, LRRK2, PINK1, PARK7 genes) explain less than 10% of familial PD [40].
For the past decade several genome-wide association studies (GWAS) have contributed to clarify
the contribution of genetic factors to the pathogenesis of PD in the Caucasian population and in
other ethnic groups [41–51]. In a recent meta-analysis of PD GWAS with over 7 million variants,
26 loci have shown significant association with PD. Replication studies confirmed 24 single nucleotide
polymorphisms (SNPs), and conditional analyses within loci showed four loci —β-Glucocerebrosidase
(GBA); Diacylglycerol kinase θ, 110kD (GAK-DGKQ); SNCA; Human leukocyte antigen (HLA)—with
a secondary independent risk variant [52]. Significant associations at different loci—Discs large
homolog of 2 (DLG2), Sipa1-like protein (SIPA1L2), Serine/Theonine kinase 39 (STK39), Vacuolar
protein sorting 13 homolog C (VPS13C), Ric-like protein without CAAX motif 2 (RIT2), BST1,
PARK16—have been found in Asians vs. Europeans, together with allelic heterogeneity at LRRK2 and
at six other loci including MAPT and GBA-SYT11 [50]. Some other candidate genes have been recently
reported to be associated with PD in different cohorts (i.e., RAD51B [39], DYRK1A [53], CHCHD2 [54],
VPS35 [55], RAB39B [56], TMEM230 [57]).
In addition to the mutations of primary genes responsible for PD-related synucleopathy,
most defective loci identified so far are linked to pathogenic pathways leading to premature
neurodegeneration in PD [51]. α-Synuclein accumulation, mitochondrial dysfunction, autophagic
impairment, and oxidative and endoplasmic reticulum stress are common findings in the PD
pathogenic cascade. The SNCA (α-synuclein) gene encodes a presynaptic protein that tends to misfold
and is subsequently found to be a major component of Lewy bodies, a histological hallmark of the
PD brain. Point mutations in the SNCA gene cause rare familial forms of PD. Duplication/triplication
of the wild type SNCA gene also causes a form of PD, indicating that increased levels of the normal
α-synuclein protein are sufficient to cause the disease. Several SNPs in the SNCA gene are associated
with an increased risk of developing sporadic PD. A GWAS has identified a novel SNP rs356182 at
SNCA that can modulate the risk of PD in Caucasian ancestry and in the Chinese population [58].
Glucocerebrosidase 1 (GBA1) mutations, resulting in misfolded glucocerebrosidase (GCase),
affect the functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. Misfolded
Int. J. Mol. Sci. 2017, 18, 551 10 of 28
GCase trapped in the ER leads to an increase in both the ubiquitin–proteasome system (UPS) and
the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or
ER-associated degradation, with subsequent increase in apoptosis. The presence of misfolded
GCase in the lysosomes together with a reduction in wild type GCase levels leads to a retardation
of α-synuclein degradation via chaperone-mediated autophagy, which results in α-synuclein
accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance
of autophagosomes, and accumulation of this cellular detritus. GBA1 mutations perturb normal
mitochondria functioning by increasing the generation of free radical species (ROS) and decreasing
ATP production, oxygen consumption, and membrane potential [59]. Furthermore, heterozygous GBA1
mutations alter the lysosomal enzyme that converts glucosyl-ceramides into ceramide, and increase
the risk of developing PD [60]. Defects in ceramide metabolism have been recognized in PD. Altered
sphingolipid composition in Lrrk2−/− mouse brains has been observed in lipidomic studies. Ceramide
levels are increased in Lrrk2−/− mice with effects on GBA1 [60].
Oxidative stress plays a central role in the progress of PD (i) affecting nucleic acid
stability by oxidizing RNA, increasing mitochondrial DNA (mtDNA) mutation, and launching
translesion synthesis (TLS); (ii) disturbing protein homeostasis by accelerating α-synuclein
aggregation, parkin aggregation, and proteasome dissociation; (iii) modulating dopamine release by
activating ATP-sensitive potassium channels (KATP ) and inactivating neuronal nicotinic acetylcholine
receptors (nAChRs); and (iv) influencing cellular self-defenses by promoting the cytoprotective
effects of oncogene DJ1(DJ-1) and phosphatase and tensin homolog PINK1 while inducing Akt
dysregulation [53,61,62]. Elevated levels of oxidative or nitrative stresses have been implicated in
α-synuclein-related toxicity. Phosphorylation of α-synuclein on serine 129 (S129) modulates autophagic
clearance of inclusions and is prominently found in Lewy bodies [63]. Mutations in the LRRK2
gene associated with PD also cause autophagy dysregulation [64]. Some studies delineating the
pathways involved in parkin/PINK1-mediated mitophagy also contributed to the renaissance of the
“mitochondrial theory of PD” [65,66]. Dysfunction of the mitochondria caused by bioenergetic defects,
mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes
in dynamics of the mitochondria such as fusion or fission, changes in size and morphology, alterations
in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the
presence of mutated proteins associated with mitochondria are implicated in PD [66].
The “proteasome theory of PD” is based on the fact that several genes with polymorphic variants
associated with different forms of PD encode proteins which are integrated in the machinery of the
proteasome system. Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the
cell, particularly in neurons, are widely thought to be protective. Parkin dysfunction represents
a predominant cause of familial parkinsonism and also a formal risk factor for the sporadic form of PD.
Parkin exerts housekeeping protein quality control roles, and regulates mitochondrial homeostasis
and stress-related signaling. Parkin functions as an E2-dependent ubiquitin ligase associated with
the UPS, a major intracellular protein degradation machinery. Parkin is also a key mammalian
regulator of mitochondrial autophagy (mitophagy). Neurodegeneration in PD patients harboring
homozygous loss-of-function mutations in the PARK2 gene may result from unbalanced levels of
ROS, which are mostly produced in mitochondria and can irreparably damage macromolecules and
trigger apoptosis [67]. Mutations in genes encoding proteins that interact with parkin in the UPS may
also contribute to PD. Mutations in PINK1 cause early onset familial PD. PINK1 accumulates on the
outer membrane of damaged mitochondria followed by recruiting parkin to promote mitophagy [65].
Mutations in the FBX07 (F-box protein 7) gene, encoding an adaptor protein in Skp–Cullin–F-box (SCF)
SCF(FBXO7) ubiquitin E3 ligase complex, to recognize substrates and mediate substrate ubiquitination
by SCF(FBXO7) E3 ligase, are also associated with PD. Parkinson’s disease-linked FBXO7 can recruit
parkin into damaged mitochondria and facilitate its aggregation [68]. Point mutations within FBXO7
map within specific functional domains, including near its F-box domain and its substrate recruiting
domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically
Int. J. Mol. Sci. 2017, 18, 551 11 of 28
linked to early-onset PD. FBXO7 negatively regulates glycogen synthase kinase 3 β (GSK3β) activity.
FBXO7 ubiquitinates translocase of outer mitochondrial membrane 20 (Tomm20), and its levels
correlate with Fbxo7 expression, indicating a stabilizing effect [69]. DJ-1, the product of the causative
gene of a familial form of PD, plays a significant role in anti-oxidative defense to protect cells from
oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys106)
under oxidative stress. oxDJ-1 is transformed into dimer and polymer forms that interact with 20S
proteasome [70].
Proteasome subunits (PSMB) and transporter associated with antigen processing (TAP) loci
located in the HLA class II region play important roles in immune response and protein degradation
in neurodegenerative diseases. Immune dysregulation, which was associated with the major
histocompatibility complex (MHC) class I pathway, may be involved in PD pathogenesis. Proteasome
subunits and TAP genes are responsible for immune activity and protein degradation in MHC
class I pathway. The classical MHC class molecules, HLA-DRB, represent the antigens for immune
effector cells associated with PD. The PSMB and TAP genes are adjacent to HLA-DR within the
HLA class II region. PSMB9 and PSMB8 encode β1i (low molecular weight protein 2) and β2i (low
molecular weight protein 7) subunits of immunoproteasome, and replace the proteasome subunits in
the ubiquitin–proteasome system as “immune” subunits. PSMB and TAP genes may be involved in
α-synuclein degradation with more genetic susceptibility to PD by regulation of immunoproteasome
in dopaminergic neurons [71].
Defects in genes responsible for pesticide metabolism (PON1), transport across the blood–brain
barrier (ABCB1), pesticides interfering with or depending on dopamine transporter activity
(DAT/SLC6A3) and dopamine metabolism (ALDH2), impacting mitochondrial function via
oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1), and contributing to immune
dysregulation (HLA-DR), may also represent additional risk factors for PD [22].
Parkinson’s disease-related pathogenic and susceptibility genes are under the influence of the
epigenetic machinery (DNA methylation, chromatin remodeling, histone modifications, miRNA
regulation) that regulates their expression in different tissues and may contribute to selective
nigrostriatal dopaminergic neurodegeneration. Epigenetic changes in PD-related genes also contribute
to PD pathogenesis and epigenetic drugs might constitute a potential therapeutic option in the
future [26,34,35,72–77].
3. Conventional Treatments
Classical therapeutic interventions for the symptomatic treatment of psychomotor dysfunction in
PD include pharmacotherapy, deep brain stimulation, and physiotherapy [78]. In addition to dopamine
precursors (L-DOPA), other symptomatic treatments for PD include dopamine agonists (amantadine,
apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine),
monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase
(COMT) inhibitors (entacapone, tolcapone) [9,15,17,19] (Table 1). The initial complication of
long-term L-DOPA therapy is the “wearing-off” phenomenon [79,80], together with motor fluctuations
and dyskinesia, which develop during the use of both L-DOPA and dopamine agonists [15,81].
Diverse dopaminergic and nondopaminergic pharmacological approaches have been developed
to manage such complications, including novel L-DOPA formulations, COMT inhibitors (opicapone),
dopamine agonists, adenosine A2A antagonists (istradefylline, preladenant, tozadenant), glutamatergic
N-methyl-D-aspartate (NMDA) antagonists, serotonergic agents (eltoprazine), and metabotropic
glutamate receptor 5 (mGluR5) modulators (mavoglurant), with controversial results [82,83].
Polypharmacy with antidepressants, antipsychotics, urological drugs, analgesics, antihistaminics and
cholinesterase inhibitors also contributes to severe complications associated with the anticholinergic
burden in PD [84]. Furthermore, gastrointestinal complications (constipation, sialorrhea, dysphagia,
difficulty in mastication, choking/aspiration) [85,86], cardiovascular problems [87,88], neuroendocrine
changes and psychiatric disorders are frequent in PD patients chronically treated with conventional
Int. J. Mol. Sci. 2017, 18, 551 12 of 28
antiparkinsonian drugs [9,85]. An additional complication is the Pisa syndrome, defined as a reversible
lateral bending of the trunk with a tendency to lean to one side [89]. It is common to administer atypical
neuroleptics (e.g., quetiapine) when PD patients develop psychotic symptoms. This pharmacological
intervention should be avoided due to the fact that most neuroleptics display an antidopaminergic
effect which may neutralize or reduce the pharmacological action of antiparkinsonian drugs,
contributing to additional psychomotor deficits.
4. Pharmacogenomics
Pharmacogenomics accounts for 60%–90% variability in the pharmacokinetics and
pharmacodynamics of antiparkinsonian drugs. Genes involved in the pharmacogenetic network
include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes [9–14] (Table 1),
and all these genes are also under the influence of epigenetic modifications (DNA methylation,
histone/chromatin remodeling, mRNA regulation) [12–14]. In recent years novel evidence
has demonstrated the impact of pharmacogenetics on antiparkinsonian drug efficacy and
safety [9,17,90–93] (Table 1). In the particular case of L-DOPA, the ANKK1, BDNF, LRRK2, and PARK2
genes are pathogenic genes potentially involved in its effects. The CCK, CCKAR, CCKBR, DRD1,
DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, and OPRM1 genes are
mechanistic genes whose products influence L-DOPA efficacy and safety. L-DOPA is a substrate of
enzymes encoded by the COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DBH, DDC,
G6PD, MAOB, TH, UGT1A1, and UGT1A9 genes responsible for its metabolism. Solute carrier family 6
member 3 (SLC6A3) is the major transporter of L-DOPA and ACE, ACHE and APOE are pleiotropic
players in L-DOPA efficacy and safety [9] (Table 1). ADORA2A SNPs and HOMER1 variants may
be associated with L-DOPA-induced dyskinesia and psychotic symptoms [94,95]. A haplotype
integrating −141C Ins/Del, rs2283265, rs1076560, C957T, TaqIA and rs2734849 polymorphisms at the
DRD2/ANKK1 gene region might also be associated with L-DOPA-induced motor dysfunction [96].
SLC6A3 is a genetic modifier of the treatment response to L-DOPA in PD [97]. The multidrug resistance
gene (MDR1) C1236T polymorphism may also influence PD pharmacotherapy [98] as well as SNPs in
genes encoding the dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter
2 (VMAT2; SLC18A2) [99]. Consequently, the personalized treatment of PD patients requires the
implementation of pharmacogenetic procedures in order to optimize therapeutics (improving efficacy
and safety) [9].
5. Novel Treatments
The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search
for novel alternatives. Some attempts have been made with novel compounds (alternative and
complementary medicines) for PD in recent times [17–19,100,101]. The revival of some classic and novel
natural products (i.e., Vicia faba, Mucuna pruriens, Siegesbeckia pubescens, Sophora flavescens, Carthamus
tinctorius, Curcuma longa, Huperzia selago, Diphasiastrum complanatum, Erythrina velutina, Gynostemma
pentaphyllum, Echinacoside, Centella asiatica, Sulforaphane, Oleuropein, flavonoids, Ginsenosides,
cyanidin-3-O-glucoside, caffeine, Resveratrol, and other polyphenols) has also been proposed; and new
applications have been submitted to the USA and European Patent Offices in this regard. Some of these
natural products with potential efficacy in PD show selective dopaminergic neuroprotection to prevent
neuronal death, with additional benefits such as antioxidant, anti-inflammatory, and neurotrophic
effects. An example of this is E-PodoFavalin-15999 (Atremorine), a novel biopharmaceutical compound,
obtained by means of non-denaturing biotechnological procedures from structural components of
Vicia faba L., for the prevention and treatment of PD [17–19,101,102]. Preclinical studies (in vitro)
revealed that Atremorine is a powerful neuroprotectant in (i) cell cultures of human neuroblastoma
SH-SY5Y cells; (ii) hippocampal slices in conditions of oxygen and glucose deprivation; and (iii)
striatal slices under conditions of neurotoxicity induced by 6-hydroxydopamine (6-OHDA). In vivo
studies showed that Atremorine (i) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Int. J. Mol. Sci. 2017, 18, 551 13 of 28
(MPTP)-induced dopaminergic neurodegeneration; (ii) inhibits MPTP-induced microglia activation

and neurotoxicity in the substantia nigra; and (iii) improves motor function in mice with MPTP-induced
neurodegeneration [17–19,101,102] (Figure 1).
Int. J. Mol. Sci. 2017, 18, 551 15 of 30
Figure 1. Effect of Atremorine (AT) treatment against dopaminergic degeneration. Comparative

Figure 1. Effect of Atremorine (AT) treatment against dopaminergic degeneration. Comparative
photomicrographs of tyrosine hydroxylase (TH) immunoreactivity were taken in the substantia nigra
photomicrographs
(SN) of mice withof tyrosine hydroxylase (TH) immunoreactivity
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were taken in
(MPTP)-induced the substantia
neurotoxicity,
nigrauntreated
(SN) of mice
(E) and treated with L-DOPA (C,D) or Atremorine (A,B). Note the remarkableneurotoxicity,
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced effect of
untreated (E) and
Atremorine treated
(A,B) with L-DOPA
in reversing (C,D) effect
the neurotoxic or Atremorine
of MPTP on (A,B). Note the neurons.
dopaminergic remarkable(A–F)effect
of Atremorine
Atremorine; (A,B) in reversing
(J–L) Atremorine the neurotoxic
+ L-DOPA; effect (P–R)
(M–O) Untreated; of MPTP
Controlon dopaminergic
+ Atremorine. Scale neurons.
bar:
(A–F)100 µm. Adapted
Atremorine; withAtremorine
(J–L) permission from Carrera et (M–O)
+ L-DOPA; al. [101]. Untreated; (P–R) Control + Atremorine.
Scale bar: 100 µm. Adapted with permission from Carrera et al. [101].
Int. J. Mol. Sci. 2017, 18, 551 14 of 28
Int. J. Mol. Sci. 2017, 18, 551 16 of 30
Clinical studies ininuntreated

Clinical studies untreatedpatients
patientswhowho receive
receive Atremorine
Atremorine for theforfirst
thetime
first(never
time treated
(never
treated before with antiparkinsonian drugs) revealed that Atremorine
before with antiparkinsonian drugs) revealed that Atremorine enhances dopaminergic enhances dopaminergic
neurotransmission
neurotransmission and andincreases
increases plasma
plasma dopamine
dopamine levelslevels by 200–500-fold
by 200–500-fold [17] (Figure[17]2).(Figure
In patients2).
In patients chronically
chronically treated withtreated
L-DOPA with -DOPA
or Lother or other antiparkinsonian
antiparkinsonian drugs, Atremorine
drugs, Atremorine induces
induces a dopamine
aresponse
dopamine of response
similar of similar magnitude
magnitude to that observed
to that observed in previously
in previously untreateduntreated patients.
patients. This
This pro-dopaminergic
pro-dopaminergic effecteffect
can can
be be attributed
attributed to tothetherich
richcontent
contentofof natural
natural L-DOPA (average(average
concentration
concentration20 20mg/g) the composition
mg/g) in the composition of Atremorine. However, the neuroprotective
neuroprotective effecteffect of
of this
this
nutraceutical
nutraceutical product on dopaminergic
dopaminergic neurons, as demonstrated in in vitro vitro studies
studies and
and inin animal
animal
models
models ofof PD
PD [17,101,102],
[17,101,102], cannot
cannot bebe attributed
attributed toto LL-DOPA
-DOPA alone,alone, but
but to
to other
other intrinsic
intrinsic constituents
constituents
(selective
(selective neurotrophic
neurotrophicfactors)
factors)of ofthe
the compound
compound [17].[17]. One
One hundred
hundred percent
percent ofUntreated
ofUntreated PD PD patients
patients
exhibit dramatic hypodopaminemia,
exhibit a dramatic hypodopaminemia,with withplasma
plasmalevels
levels of of dopamine
dopamine (DA)
(DA) below
below 20 pg/mL,
20 pg/mL, and
and PD patients
PD patients under under long-term
long-term treatment
treatment with with
L-DOPA L -DOPA
and/or and/or conventional
conventional antiparkinsonian
antiparkinsonian drugs
drugs experience
experience a hyperdopaminemic
a hyperdopaminemic status whichstatus which
might might be responsible
be responsible for (i)improvement
for (i) the clinical the clinical
improvement
of PD cardinalofsymptoms
PD cardinal insymptoms in the(ii)
the short term; short
theterm; (ii) the “wearing-off”
“wearing-off” phenomenon phenomenon
[79,80]; (iii)[79,80];
motor
(iii) motor fluctuations
fluctuations and dyskinesia
and dyskinesia [15,81];[15,81];
(iv) (iv) systemic
systemic complications(gastrointestinal
complications (gastrointestinal disorders,
cardiovascular
cardiovascular problems,
problems, hormonal
hormonal dysregulation)
dysregulation) [85–87];
[85–87]; and (v) (v) neuropsychiatric
neuropsychiatric disorders
disorders
(depression,
(depression, anxiety,
anxiety,toxic
toxicpsychosis)
psychosis)[9,103].
[9,103].
Figure 2.2.Atremorine-induced
Figure Atremorine-induceddopamine
dopamine (DA)
(DA) response
response in patients
in patients with with Parkinsonian
Parkinsonian disorders.
disorders. DAb:
DAb: Basal dopamine levels; DAt: Plasma dopamine levels one hour after Atremorine administration
Basal dopamine levels; DAt: Plasma dopamine levels one hour after Atremorine administration (5 g,
(5 g, p.o.).
p.o.). Adapted
Adapted with permission
with permission from from Cacabelos
Cacabelos et al. [18].
et al. [18].
Atremorine is an option to minimize the “wearing-off” phenomenon, extending the therapeutic

Atremorine is an option to minimize the “wearing-off” phenomenon, extending the therapeutic
effect of conventional antiparkinsonian drugs, and reducing potential side effects, since the
effect of conventional antiparkinsonian drugs, and reducing potential side effects, since the
co-administration of Atremorine with other antiparkinsonian drugs allows a dose reduction of
co-administration of Atremorine with other antiparkinsonian drugs allows a dose reduction of
conventional drugs by 25%–50% with enhancement of clinical benefits and reduction of short- and
conventional drugs by 25%–50% with enhancement of clinical benefits and reduction of short- and
long-term adverse drug reactions [19].
long-term adverse drug reactions [19].
Atremorine is a powerful enhancer of plasma catecholamines (noradrenaline, adrenaline,
Atremorine is a powerful enhancer of plasma catecholamines (noradrenaline, adrenaline,
dopamine), with no apparent effect on serotonin [18]. Catecholamines are processed by three main
dopamine), with no apparent effect on serotonin [18]. Catecholamines are processed by three main
nuclei (A8-retrobulbal, A9-substantia nigra pars compacta, A10-ventral tegmental area) arranged in
nuclei (A8-retrobulbal, A9-substantia nigra pars compacta, A10-ventral tegmental area) arranged
the mesencephalic region where the mesostriatal, mesolimbic and mesocortical pathways are
organized [104,105]. Midbrain dopaminergic neurons in the ventral tegmental area and
Int. J. Mol. Sci. 2017, 18, 551 15 of 28
in the mesencephalic region where the mesostriatal, mesolimbic and mesocortical pathways are
organized [104,105]. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic
neurons in the locus coeruleus are major sources of dopamine and noradrenaline to the prefrontal
cortex, where these amines regulate cognition, behavior, and psychomotor function [106,107].
Noradrenaline, adrenaline, dopamine and serotonin play a central role in CNS and gut pathophysiology.
Dopamine and noradrenaline are involved in the chemical structure of neuromelanins in the
substantia nigra and the locus coeruleus, respectively. Dopamine, 3,4-dihydroxyphenylacetic
acid (DOPAC), 3,4-dihydroxyphenylethanol (DOPE), and 3,4-dihydroxyphenylalanine (DOPA) are
mainly responsible for the structure of neuromelanin from substantia nigra, while noradrenaline,
3,4-dihydroxymandelic acid (DOMA), and 3,4-dihydroxyphenylethylene glycol (DOPEG) are
responsible for the structure of neuromelanin from locus coeruleus [108]. Deficiencies in these
monoamines are currently found in PD [109,110]. Monoamine transporters (MATs) that facilitate
the reuptake of noradrenaline, dopamine, and serotonin are sodium-coupled transport proteins
belonging to the neurotransmitter/Na+ symporter (NSS) family, which have also been implicated
in PD [111,112]. Hypoactivity of the dopaminergic and noradrenergic systems in the brain
stem are related to non-motor and motor symptoms in PD [113,114]. Dysregulation of these
neurotransmitters is also involved in a variety of gastrointestinal symptoms in PD [115], and all
of them appear to contribute to neurotransmitter and autonomic dysfunctions in PD [113], including
mechanisms of L-DOPA-induced dyskinesia [115,116] and cardiovascular dysautonomia [117].
Therefore, appropriate doses of Atremorine alone or in combination with low doses of conventional
antiparkinsonian drugs [118] may benefit PD patients in whom the biosynthetic apparatus of the
catecholaminergic system is damaged, including tyrosine hydroxylase (TH), the tetrahydrobiopterin
(BH4) cofactor of TH, and the activity of the BH4-synthesizing enzyme, GTP cyclohydrolase
I (GCHI), as well as the activities of aromatic L-amino acid decarboxylase (AADC, DOPA
decarboxylase), DBH, and phenylethanolamine N-methyltransferase (PNMT), which synthesize
dopamine, noradrenaline, and adrenaline, respectively [119]. Atremorine may also neutralize the
apoptosis of nigrostriatal dopamine neurons which, in post-mortem studies, show increased levels
of pro-inflammatory cytokines—tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)—, increased
levels of apoptosis-related factors—p 55, soluble Fas, B-cell lymphoma 2 (Bcl-2), caspases 1-2—,
and decreased levels of neurotrophins (BDNF) [119].
The increase in noradrenaline induced by Atremorine may contribute to clinical improvement
and neuroprotection, since noradrenergic neuronal loss in the locus coeruleus is exacerbated in PD.
Lewy pathology in the locus coeruleus, the brain’s main source of noradrenaline, precedes that of the
substantia nigra and may be one of the very first pathogenic events in PD. Oxidized noradrenaline
exerts a neuroprotective effect and may even prevent the formation of toxic and higher molecular
weight α-synuclein oligomers associated with PD. Noradrenergic neurons innervate the substantia
nigra. The locus coeruleus orchestrates the other major catecholaminergic nuclei, such as the substantia
nigra and raphe nuclei. In this regard, it has been suggested that neuronal loss in the locus coeruleus
and the accompanying noradrenergic deficiency constitute an important pharmacological target for
the treatment of PD [120]. Noradrenaline exerts critical effects in the modulation of different types
of behavior (sleep-wakefulness cycle, depression, anxiety), psychomotor function, anti-inflammatory
responses in glial cells, neurotrophic activity, and neuroprotection against oxidative stress-related free
radical formation [121,122]. Preclinical studies showed that Atremorine displays powerful antioxidant,
anti-inflammatory, and neuroprotective effects [102], some of which might be associated with its
effect as a noradrenergic enhancer. Since premature noradrenaline deficiency resulting from selective
degeneration of neurons of the locus coeruleus and sympathetic ganglia may be a praecox event
in PD [123,124], the noradrenergic effects of Atremorine may also explain, in part, its clinical and
biochemical benefits [17,18].
Int. J. Mol. Sci. 2017, 18, 551 16 of 28
The midbrain dopaminergic system is regulated by the central adrenergic system [125].
The moderate increase in adrenaline levels observed after Atremorine administration may also
contribute to enhancing dopaminergic neurotransmission in PD [18].
Neuroendocrine dysfunction and alterations in circadian rhythms are frequently seen in patients
with PD, but most results are contradictory, with no clear definition between basal conditions
and drug-induced modifications in hypothalamus-pituitary neuropeptides and hormones [126–128].
Furthermore, prolactin and growth hormone (GH) secretion are directly regulated by hypothalamic
and supra-hypothalamic dopaminergic mechanisms [129–131]. Some studies reported higher levels of
prolactin and GH in PD patients as compared with controls [128,132]. In patients with multiple system
atrophy, in whom there is a reported loss of hypothalamic dopamine, basal prolactin levels are elevated,
L-DOPA increases GH secretion, and the neuroendocrine response to L-DOPA is unclear [133], differing
from endocrine responses in PD patients [134,135]. 6-Pyruvoyl-tetrahydropterin synthase (PTPS)
deficiency is a BH4 deficiency with hyperphenylalaninemia, which is treated with L-DOPA/Carbidopa,
5-hydroxytryptophan (5-HTP) and BH4. In these patients, serum prolactin levels are elevated due to
their hypodopaminergic condition, and the administration of L-DOPA reduces prolactin secretion [136].
In healthy subjects, acute L-DOPA and exercise release GH, but in PD patients this response is
delayed [137]. In animal studies, L-DOPA causes a decrease in prolactin response, whereas cortisol
levels tend to increase [138]. It has also been postulated that peripheral noradrenergic terminals may
contribute to regulating prolactin secretion [139].
Atremorine induces a significant decrease in prolactin, GH, and cortisol levels [18]. The prolactin
and GH response to Atremorine can be directly attributed to the effect of L-DOPA on dopamine
and noradrenaline synthesis and release, with the consequent increase in central and peripheral
dopamine and noradrenaline levels. In contrast, the effect on cortisol might be primarily influenced by
a direct effect of dopamine, noradrenaline and adrenaline on the adrenal gland, and secondarily by
pituitary and/or hypothalamic regulation of adrenocorticotropic hormone (ACTH), which in plasma
did not show any significant changes. Neuroendocrine function in PD is still poorly understood,
and the investigation of differences in PD-related basal neuroendocrine conditions vs antiparkinsonian
drug-induced neuroendocrine changes deserves further studies.
Other non-motor symptoms present in PD, such as constipation and other alterations in
gastrointestinal motility mediated via catecholaminergic mechanisms [80,140], might also be alleviated
by Atremorine. However, further investigation is needed on the central and peripheral effects
of Atremorine, especially taking into account that the effects of Atremorine are genotype-related,
involving both pathogenic genes associated with neurodegeneration, and genes of the cytochrome
P450 family associated with drug metabolism [17,19].
All these data together clearly indicate that Atremorine is a very safe bioproduct in PD,
with a powerful effect on catecholamines, especially dopamine and, to a lesser extent, noradrenaline.
The effect of Atremorine on adrenaline is very modest, and no effect on serotonin levels can be
detected one hour after oral administration. The effect of Atremorine on prolactin and GH is likely
to result from the primary consequence of hypothalamic regulation mediated via dopaminergic
and noradrenergic neurotransmission, and secondarily as a direct effect on the pituitary gland.
In contrast, the effect on cortisol might result primarily from a direct effect on the adrenal gland,
and secondarily from the hypothalamus–hypophyseal regulation of ACTH. According to these results,
Atremorine may help to optimize neuroendocrine function in PD, especially in those patients with
somatotropinergic, lactotropinergic and corticotropinergic dysregulation. The effects of Atremorine on
plasma catecholamines might also be beneficial for PD patients with cardiovascular dysautonomia.
However, although the dopaminergic surge induced by Atremorine is proportional to basal
DA levels in PD patients, with a potential 200–500-fold increase over basal levels, its real potency
and pharmacodynamic and pharmacokinetic properties are highly influenced by genetic and
pharmacogenetic factors [17] (Figures 3–6). The condition of extensive (EM), intermediate (IM),
poor (PM) or ultra-rapid metabolizer (UM) associated with different CYP variants, and the inheritance
Int. J. Mol. Sci. 2017, 18, 551 17 of 28
of the APOE-4 allele as well, influence the Atremorine-induced dopamine response in PD patients [17].
Although practically 100% of the patients respond to Atremorine, the magnitude of the response
is modulated by the pharmacogenetic profile of each patient. For instance, in absolute values,
CYP2D6-PMs exhibit the lowest basal dopamine levels and a response to Atremorine which is lower
than that of CYP2D6-EMs or IMs; however, CYP2D6-UMs show the highest basal dopamine levels and
the most spectacular response to Atremorine [17] (Figure 3). The three major CYP2C19 genophenotypes
show aInt. J. Mol. Sci.
similar 2017, 18, 551
response to Atremorine (Figure 4); in contrast, comparatively, CYP2C9-IMs 19 of 30
(Figure 5)
and CYP3A4/5-IMs (Figure 6) are the best responders and CYP2C9-PMs and CYP3A4/5-RMs are
CYP2C9-IMs (Figure 5) and CYP3A4/5-IMs (Figure 6) are the best responders and CYP2C9-PMs and
the worst respondersare
CYP3A4/5-RMs to the
Atremorine, though
worst responders to all genophenotypes
Atremorine, though allrespond with a respond
genophenotypes significant
withsurge
a in
dopamine levels one hour after Atremorine administration (5 g, p.o.) [17].
significant surge in dopamine levels one hour after Atremorine administration (5 g, p.o.) [17].
Figure 3. CYP2D6-related Atremorine-induced dopamine response. Basal (DAb) and Atremorine-

Figure 3. CYP2D6-related Atremorine-induced dopamine response. Basal (DAb) and Atremorine-
induced dopamine response (DAt) in CYP2D6 extensive (EM), intermediate (IM), poor (PM), and
induced dopamine response (DAt) in CYP2D6 extensive (EM), intermediate (IM), poor (PM),
ultra-rapid metabolizers (UM). Adapted with permission from Cacabelos et al. [17].
and ultra-rapid metabolizers (UM). Adapted with permission from Cacabelos et al. [17].
Int. J. Mol. Sci. 2017, 18, 551 18 of 28
Int. J. Mol. Sci. 2017, 18, 551 20 of 30
Figure
Figure 4. 4. CYP2C19-relatedAtremorine-induced
CYP2C19-related Atremorine-induced dopamine
dopamine response.
response.BasalBasal(DAb)
(DAb)and Atremorine-
and Atremorine-
induced dopamine response (DAt) in CYP2C19 extensive (EM), Intermediate (IM), and Ultra-rapid
induced dopamine response (DAt) in CYP2C19 extensive (EM), Intermediate (IM), and Ultra-rapid
metabolizers (UM). Adapted with permission from Cacabelos et al. [17].
metabolizers (UM). Adapted with permission from Cacabelos et al. [17].
Int. J. Mol. Sci. 2017, 18, 551 19 of 28
Int. J. Mol. Sci. 2017, 18, 551 21 of 30
Figure
Figure 5. CYP2C9-related
5. CYP2C9-related Atremorine-induced
Atremorine-induced dopaminedopamine response.
response. Basal (DAb)Basaland
(DAb) and
Atremorine-
Atremorine-induced dopamine response (DAt) in CYP2C9 extensive (EM), Intermediate (IM),
induced dopamine response (DAt) in CYP2C9 extensive (EM), Intermediate (IM), and Poor metabolizers and
Poor
(PM). metabolizers
Adapted (PM). Adapted
with permission fromwith permission
Cacabelos from
et al. [17].Cacabelos et al. [17].
Int. J. Mol. Sci. 2017, 18, 551 20 of 28
Int. J. Mol. Sci. 2017, 18, 551 22 of 30
Figure
Figure 6. 6. CYP3A4/5-relatedAtremorine-induced
CYP3A4/5-related Atremorine-induced dopamine
dopamineresponse.
response.Basal (DAb)
Basal and
(DAb) Atremorine-
and Atremorine-
induced dopamine response (DAt) in CYP3A4/5 extensive (EM), intermediate (IM),and
induced dopamine response (DAt) in CYP3A4/5 extensive (EM), intermediate (IM), andrapid
rapid
metabolizers (RM). Adapted with permission from Cacabelos et al. [17].
metabolizers (RM). Adapted with permission from Cacabelos et al. [17].
6. Further
6. Further Considerations
Considerations
Cardiovascular dysfunction is a common finding in PD patients. When PD patients are stratified
Cardiovascular dysfunction is a common finding in PD patients. When PD patients are stratified
by their cardiovascular function, as assessed with electrocardiogram (EKG), 39.50% show an
by their cardiovascular function, as assessed with electrocardiogram (EKG), 39.50% show an abnormal
abnormal EKG, 19.32% are borderline, and 41.18% exhibit a normal EKG [141].
EKG, 19.32% are borderline, and 41.18% exhibit a normal EKG [141].
Cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in
Cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in
parallel with cardiac sympathetic dysfunction [88]. Low plasma levels of noradrenaline and
parallel with cardiac sympathetic dysfunction [88]. Low plasma levels of noradrenaline and adrenaline,
Int. J. Mol. Sci. 2017, 18, 551 21 of 28
secondary to the loss of catecholaminergic neurons in the rostral ventrolateral medulla, together
with loss of nigral dopaminergic neurons, may be responsible for reduced sympathetic activity [142]
and cardiovascular dysautonomia in PD [117]. Parkinson’s disease patients with abnormal EKG
have lower levels of dopamine, and the basal levels of noradrenaline are substantially different
between cases with abnormal vs normal EKG [18,141]. The administration of Atremorine tends to
increase the plasma levels of the three catecholamines, with the highest impact on dopamine levels,
and a minimum effect on adrenaline levels [18]. Basal biochemical conditions and cardiovascular
function have been evaluated in PD patients without any treatment at the moment of their first
diagnosis, and in PD patients chronically treated with antiparkinsonian drugs for more than one year.
Both groups exhibited substantial biochemical and cardiovascular differences. In addition to changes
in blood biochemical (i.e., urea, creatinine, phosphorous, alkaline phosphatase, folate, cyanocobalamin)
and hematological parameters (neutrophils, basophils) [17], the most significant differences were
found in plasma neurotransmitters and hormones. For instance, as expected, basal dopamine levels
in untreated patients were below 20 pg/mL (11.22 ± 0.29 pg/mL; mean ± standard error (SE))
whereas basal dopamine levels in treated patients ranged from 21 to 30,000 pg/mL (2139.23 ± 804.72
pg/mL; mean ± SE) (p < 0.001) [17,18]. Chronic treatment with antiparkinsonian drugs reduces
the levels of plasma serotonin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and
estrogen, and tends to increase the levels of adrenaline, histamine, ACTH, cortisol, and testosterone
in a non-significant mode [18]. Changes in neurotransmitters and endocrine parameters are highly
influenced by the genomic profile of each patient [17–19].
Since PD patients undergo long-term periods of treatment with different antiparkinsonian drugs,
which chronically alter neurotransmitter levels and hormonal regulation, some reflections are pertinent:
(i) it is likely that the chronic overstimulation of the dopaminergic system at central and peripheral
levels may become deleterious for cardio-cerebrovascular function and hormonal regulation; (ii) since
the central dopaminergic dysfunction precedes the clinical onset of the disease by several decades,
it is urgent to identify predictive biomarkers to protect the population at risk of suffering PD; (iii) the
progression of PD over the past 50 years, in terms of gradual increase in prevalence and incidence
rates, indicates that environmental toxicity may contribute to accelerating selective dopaminergic
neurodegeneration; therefore, a better scrutiny of environmental risk factors is necessary to implement
preventive programs in susceptible persons; (iv) most post-mortem neurochemical studies might be
contaminated by chronic polypharmacy; (v) novel drugs and bioproducts for the treatment of PD
should address dopaminergic neuroprotection to reduce premature neurodegeneration rather than
dopaminergic overstimulation; and (vi) since biochemical changes and therapeutic outcomes are
highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on
pharmacogenetic procedures to optimize therapeutics [16].
Modern neuroscience must embrace the idea that most brain disorders require
more neuroprotection and fewer symptomatic repressors. Unfortunately, the history of
neuropsychopharmacology is a history of chemical symptomatic repression with delayed
consequences for patients and society in terms of chronic disability, family burden, and health
costs. In the particular case of Parkinson’s disease, future challenges are (i) a better insight into the
pathogenesis of premature dopaminergic neurodegeneration; (ii) the identification of biomarkers
for an early diagnosis; (iii) the implementation of preventive programs to halt disease progression
at pre-symptomatic stages; (iv) the development of novel antiparkinsonian drugs with specific
neuroprotective effects on the dopaminergic system; and (v) the personalized treatment of PD patients.
Conflicts of Interest: The author is President of EuroEspes.

Int. J. Mol. Sci. 2017, 18, 551 22 of 28
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© 2017 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access
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Parkinson's Disease: From Pathogenesis To Pharmacogenomics: Molecular Sciences

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Parkinson's Disease: From Pathogenesis To Pharmacogenomics: Molecular Sciences

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International Journal of

Academic Editor: Sabrina Angelini

Keywords: adrenaline; antiparkinsonian drugs; Atremorine; dopamine; genomics; growth hormone;

Int. J. Mol. Sci. 2017, 18, 551; doi:10.3390/ijms18030551 www.mdpi.com/journal/ijms

Name: Ropinirole; 91374-21-9; Ropinirole; ReQuip; Ropinirol;

Pathogenic genes: ANKK1, BDNF, LRRK2

(MPTP)-induced dopaminergic neurodegeneration; (ii) inhibits MPTP-induced microglia activation

Figure 1. Effect of Atremorine (AT) treatment against dopaminergic degeneration. Comparative

Clinical studies ininuntreated

Atremorine is an option to minimize the “wearing-off” phenomenon, extending the therapeutic

Figure 3. CYP2D6-related Atremorine-induced dopamine response. Basal (DAb) and Atremorine-

Conflicts of Interest: The author is President of EuroEspes.

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