Dopamine receptor D1

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Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded
by the DRD1 gene.[1][2][3]

Contents

 1Tissue distribution

 2Function

 3Production

 4Ligands

o 4.1Agonists

 4.1.1List of D1 receptor agonists

o 4.2Antagonists

 4.2.1List of D1 receptor antagonists

o 4.3Modulators

 5Protein–protein interactions

o 5.1Receptor oligomers

 6See also

 7References

 8External links

Tissue distribution
Based upon Northern blot and in situ hybridization, DRD1 mRNA expression in the central
nervous system is highest in the dorsal striatum (caudate and putamen) and ventral
striatum (nucleus accumbens and olfactory tubercle).[4] Lower levels of DRD1 mRNA
expression occur in the basolateral amygdala, cerebral cortex, septum, thalamus,
and hypothalamus.[4]

Function

The D1 subtype of the dopamine receptor is the most abundant dopamine receptor in the
central nervous system. This G-protein coupled receptor is Gs/a coupled and indirectly

activates cyclic AMP-dependent protein kinase, stimulating the neuron. D1 receptors

regulate neuronal growth and development, mediate some behavioral responses, and

modulate dopamine receptor D2-mediated events.[5] Alternative transcription initiation sites

result in two transcript variants of the gene.[6] D1-D2 dopamine receptor
heteromer formation is observed.

Production
The DRD1 gene expresses primarily in the caudate putamen in humans, and in
the caudate putamen, the nucleus accumbens and the olfactory tubercle in mouse. Gene
expression patterns from the Allen Brain Atlases in mouse and human can be found here.

Ligands

There are a number of ligands selective for the D1 receptors. To date, most of the
known ligands are based on dihydrexidine or the prototypical benzazepine partial
agonist SKF-38393 (one derivative being the prototypical antagonist SCH-23390).
[7]
D1 receptor has a high degree of structural homology to another dopamine

receptor, D5, and they both bind similar drugs.[8] As a result, none of the known

orthosteric ligands is selective for the D1 vs. the D5 receptor, but the benzazepines

generally are more selective for the D1 and D5 receptors versus the D2-like family.
[7]
Some of the benzazepines have high intrinsic activity whereas others do not. In 2015

the first positive allosteric modulator for the human D1 receptor was discovered by high-
throughput screening.[9]
Agonists
File:D1 agonists.pngChemical structures of selective D1 receptor agonists.[10][11]

Several D1 receptor agonists are used clinically. These

include apomorphine, pergolide, rotigotine, and terguride. All of these drugs are

preferentially D2-like receptor agonists. Fenoldopam is a selective D1 receptor partial

agonist that does not cross the blood-brain-barrier and is used intravenously in the
treatment of hypertension. Dihydrexidine and adrogolide (ABT-431) (a prodrug of A-

86929 with improved bioavailability) are the only selective, centrally active D1-like
receptor agonists that have been studied clinically in humans.[12] The selective

D1 agonists give profound antiparkinson effects in humans and primate models of PD,
and yield cognitive enhancement in many preclinical models and a few clinical trials.
The most dose-limiting feature is profound hypotension, but the clinical development was
impeded largely by lack of oral bioavailability and short duration of action.[12][13][14] In 2017,
Pfizer made public information about pharmaceutically-acceptable non-catechol

selective D1 agonists that are in clinical development.

List of D1 receptor agonists

 Dihydrexidine derivatives

o A-86929 - full agonist with 14-fold selectivity for D1-like receptors over

D2[7][11][15]

o Dihydrexidine - full agonist with 10-fold selectivity for D1-like receptors

over D2 that has been in Phase IIa clinical trials as a cognitive enhancer.
[16][17]
It also showed profound antiparkinson effects in MPTP-treated
primates,[18] but caused profound hypotension in one early clinical trial
in Parkinson's disease.[7] Although dihydrexidine has significant

D2 properties, it is highly biased at D2 receptors and was used for the

first demonstration of functional selectivity[19] with dopamine receptors.[20][21]

o Dinapsoline - full agonist with 5-fold selectivity for D1-like receptors over

D2[7]

o Dinoxyline - full agonist with approximately equal affinity for D1-like and

D2 receptors[7]

o Doxanthrine - full agonist with 168-fold selectivity for D1-like receptors

over D2[7]
 Benzazepine derivatives

o SKF-81297 - 200-fold selectivity for D1 over any other receptor[7]

o SKF-82958 - 57-fold selectivity for D1 over D2[7]

o SKF-38393 - very high selectivity for D1 with negligible affinity for any
other receptor[7]

o Fenoldopam - highly selective peripheral D1 receptor partial agonist used

clinically as an antihypertensive[7]

o 6-Br-APB - 90-fold selectivity for D1 over D2[7]

  Others
o Stepholidine - alkaloid with D1 agonist and D2 antagonist properties,
showing antipsychotic effects
o A-68930
o A-77636
o CY-208,243 - high intrinsic activity partial agonist with moderate selectivity

for D1-like over D2-like receptors, member of ergoline ligand family

like pergolide and bromocriptine.
o SKF-89145
o SKF-89626
o 7,8-Dihydroxy-5-phenyl-octahydrobenzo[h]isoquinoline: extremely potent,
high-affinity full agonist[22]

o Cabergoline - weak D1 agonism, highly selective for D2, and various

serotonin receptors

o Pergolide - (similar to cabergoline) weak D1 agonism, highly selective for

D2, and various serotonin receptors

Antagonists

Many typical and atypical antipsychotics are D1 receptor antagonists in addition to

D2 receptor antagonists. No other D1 receptor antagonists have been approved for

clinical use. Ecopipam is a selective D1-like receptor antagonist that has been studied
clinically in humans in the treatment of a variety of conditions,
including schizophrenia, cocaine abuse, obesity, pathological gambling, and Tourette's
syndrome, with efficacy in some of these conditions seen. The drug produced mild-to-
moderate, reversible depression and anxiety in clinical studies however and has yet to
complete development for any indication.

List of D1 receptor antagonists

 Benzazepine derivatives

o SCH-23,390 - 100-fold selectivity for D1 over D5[7]

o SKF-83,959 - 7-fold selectivity for D1 over D5 with negligible affinity for

other receptors;[7] acts as an antagonist at D1 but as an agonist at D5

o Ecopipam (SCH-39,166) - a selective D1/D5 antagonist that was being

developed as an anti-obesity medication but was discontinued[7]
Modulators
 DETQ − PAM[23][24][25]

Protein–protein interactions

Dopamine receptor D1 has been shown to interact with:

 COPG2,[26]
 COPG,[26] and
 DNAJC14.[27]
Receptor oligomers

The D1 receptor forms heteromers with the following receptors: dopamine D2 receptor,
[28]
dopamine D3 receptor,[28][29] histamine H3 receptor,[30] μ opioid receptor,[31] NMDA receptor,
[28]
and adenosine A1 receptor.[28]

 D1–D2 receptor complex[28]

 D1−H3−NMDAR receptor complex − a target to prevent neurodegeneration[32]

 D1–D3 receptor complex[28]

 D1–NMDAR receptor complex[28]

 D1–A1 receptor complex[28]

See also

 Dopamine receptor

References

1. ↑ Dearry A, Gingrich JA, Falardeau P, Fremeau RT, Bates MD, Caron MG (September 1990).
"Molecular cloning and expression of the gene for a human D1 dopamine
receptor". Nature. 347 (6288): 72–6. doi:10.1038/347072a0. PMID 2144334.
2. ↑ Zhou QY, Grandy DK, Thambi L, Kushner JA, Van Tol HH, Cone R, Pribnow D, Salon J,
Bunzow JR, Civelli O (September 1990). "Cloning and expression of human and rat
D1dopamine receptors". Nature. 347 (6288): 76–80. doi:10.1038/347076a0. PMID 2168520.
3. ↑ Sunahara RK, Niznik HB, Weiner DM, Stormann TM, Brann MR, Kennedy JL, Gelernter
JE, Rozmahel R, Yang YL, Israel Y (September 1990). "Human dopamine D1 receptor
encoded by an intronless gene on chromosome 5". Nature. 347 (6288): 80–
3. doi:10.1038/347080a0. PMID 1975640.
4. ↑ Jump up to:4.0 4.1 Schetz JA, Sibley DR (2007). "Chapter 7: Dopaminergic Neurotransmission". In
Sibley DR. Handbook of Contemporary Neuropharmacology. Hoboken, NJ: Wiley-
Interscience. p. 226. ISBN 9780471660538. Localization of the D1 receptor messenger
ribonucleic acid (mRNA) expression has been mapped using Northern analysis and in situ
hybridization (for a review, see [54]). Expression of D1 receptor mRNA is highest in the
caudate putamen, nucleus accumbens, and olfactory tubercle. Lower levels of expression are
found in the basolateral amygdala, cerebral cortex, septum, thalamus, and hypothalamus.
5. ↑ ML Paul; AM Graybiel; JC David; HA Robertson (1992). "D1-like and D2-like dopamine
receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a
rat model of Parkinson's disease". The Journal of Neuroscience. 12 (10): 3729–3742.
6. ↑ "Entrez Gene: DRD1 dopamine receptor D1".
7. ↑ Jump up to:7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 Zhang J, Xiong B, Zhen X, Zhang A (2009).
"Dopamine D1 receptor ligands: where are we now and where are we going". Med Res
Rev. 29 (2): 272–294. doi:10.1002/med.20130. PMID 18642350.
8. ↑ Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J,
Van Tol HH, Niznik HB (1991). "Cloning of the gene for a human dopamine D5 receptor with
higher affinity for dopamine than D1". Nature. 350 (6319): 614–
9. doi:10.1038/350614a0. PMID 1826762.
9. ↑ Lewis MA, Hunihan L, Watson J, Gentles RG, Hu S, Huang Y, Bronson J, Macor JE, Beno
BR, Ferrante M, Hendricson A, Knox RJ, Molski TF, Kong Y, Cvijic ME, Rockwell KL, Weed
MR, Cacace AM, Westphal RS, Alt A, Brown JM (2015). "Discovery of D1 Dopamine
Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification
of Residues that Regulate Species Selectivity". J. Pharmacol. Exp. Ther. 354 (3): 340–
9. doi:10.1124/jpet.115.224071. PMID 26109678.
10. ↑ Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (November 2006).
"trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis,
resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor
full agonist". J. Med. Chem. 49 (23): 6848–57. doi:10.1021/jm0604979. PMID 17154515.
11. ↑ Jump up to:11.0 11.1 Michaelides MR, Hong Y, DiDomenico S, Asin KE, Britton DR, Lin CW, Williams
M, Shiosaki K (1995). "(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-
1- ena[c]-phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1agonist that
maintains behavioral efficacy following repeated administration and characterization of its
diacetyl prodrug (ABT-431)". J. Med. Chem. 38 (18): 3445–
7. doi:10.1021/jm00018a002. PMID 7658429.
12. ↑ Jump up to:12.0 12.1 Rosell, Daniel R; Zaluda, Lauren C; McClure, Margaret M; Perez-Rodriguez, M
Mercedes; Strike, K Sloan; Barch, Deanna M; Harvey, Philip D; Girgis, Ragy R; Hazlett, Erin
A; Mailman, Richard B; Abi-Dargham, Anissa; Lieberman, Jeffrey A; Siever, Larry J
(2014). "Effects of the D1 Dopamine Receptor Agonist Dihydrexidine (DAR-0100A) on Working
Memory in Schizotypal Personality Disorder". Neuropsychopharmacology. 40 (2): 446–
453. doi:10.1038/npp.2014.192. ISSN 0893-133X. PMC 4443959. PMID 25074637.
13. ↑ Blanchet PJ, Fang J, Gillespie M, Sabounjian L, Locke KW, Gammans R, Mouradian MM,
Chase TN (1998). "Effects of the full dopamine D1 receptor agonist dihydrexidine in
Parkinson's disease". Clin Neuropharmacol. 21 (6): 339–43. PMID 9844789.
14. ↑ Giardina, William J.; Williams, Michael (2006). "Adrogolide HCl (ABT-431; DAS-431), a
Prodrug of the Dopamine D1 Receptor Agonist, A-86929: Preclinical Pharmacology and
Clinical Data". CNS Drug Reviews. 7 (3): 305–316. doi:10.1111/j.1527-
3458.2001.tb00201.x. ISSN 1080-563X. PMID 11607045.
15. ↑ Yamashita M, Yamada K, Tomioka K (2004). "Construction of arene-fused-piperidine motifs
by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric
synthesis of a dopamine D1 full agonist, A-86929". J. Am. Chem. Soc. 126 (7): 1954–
5. doi:10.1021/ja031760n. PMID 14971926.
16. ↑ Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, Nahas Z, Kozel FA,
Kose S, Knable M, Fernandes P, Nichols DE, Mailman RB, George MS (2007). "A single 20
mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal
perfusion in schizophrenia". Schizophr. Res. 94 (1–3): 332–
341. doi:10.1016/j.schres.2007.03.033. PMID 17596915.
17. ↑ George MS, Molnar CE, Grenesko EL, Anderson B, Mu Q, Johnson K, Nahas Z, Knable M,
Fernandes P, Juncos J, Huang X, Nichols DE, Mailman RB (2007). "A single 20 mg dose of
dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with
schizophrenia". Schizophr. Res. 93 (1–3): 42–
50. doi:10.1016/j.schres.2007.03.011. PMID 17467956.
18. ↑ Taylor JR, Lawrence MS, Redmond DE, Elsworth JD, Roth RH, Nichols DE, Mailman RB
(1991). "Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in
monkeys". Eur J Pharmacol. 199 (3): 389–391. doi:10.1016/0014-2999(91)90508-
N. PMID 1680717.
19. ↑ Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA,
Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (January 2007).
"Functional selectivity and classical concepts of quantitative pharmacology". J. Pharmacol.
Exp. Ther. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID 16803859.
20. ↑ Mottola DM, Kilts JD, Lewis MM, Connery HS, Walker QD, Jones SR, Booth RG, Hyslop
DK, Piercey M, Wightman RM, Lawler CP, Nichols DE, Mailman RB (June 2002). "Functional
selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2
receptors linked to adenylate cyclase". J. Pharmacol. Exp. Ther. 301 (3): 1166–
78. doi:10.1124/jpet.301.3.1166. PMID 12023552.
21. ↑ Kilts JD, Connery HS, Arrington EG, Lewis MM, Lawler CP, Oxford GS, O'Malley KL, Todd
RD, Blake BL, Nichols DE, Mailman RB (June 2002). "Functional selectivity of dopamine
receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and
pituitary lactotrophs". J. Pharmacol. Exp. Ther. 301 (3): 1179–
89. doi:10.1124/jpet.301.3.1179. PMID 12023553.
22. ↑ Bonner LA, Chemel BR, Watts VJ, Nichols DE (September 2010). "Facile synthesis of
octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists". Bioorg. Med.
Chem. 18 (18): 6763–70. doi:10.1016/j.bmc.2010.07.052. PMC 2941879. PMID 20709559.
23. ↑ Svensson KA, Heinz BA, Schaus JM, et al. (2017). "An Allosteric Potentiator of the Dopamine
D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or
Tachyphylaxis". J. Pharmacol. Exp. Ther. 360 (1): 117–
128. doi:10.1124/jpet.116.236372. PMC 5193077. PMID 27811173.
24. ↑ Bruns RF, Mitchell SN, Wafford KA, et al. (2018). "Preclinical profile of a dopamine D1
potentiator suggests therapeutic utility in neurological and psychiatric
disorders". Neuropharmacology. 128: 351–
365. doi:10.1016/j.neuropharm.2017.10.032. PMID 29102759.
25. ↑ Wang X, Heinz BA, Qian YW, et al. (2018). "Intracellular Binding Site for a Positive
Allosteric Modulator of the Dopamine D1 Receptor". Mol. Pharmacol. 94 (4): 1232–
1245. doi:10.1124/mol.118.112649. PMID 30111649.
26. ↑ Jump up to:26.0 26.1 Bermak JC, Li M, Bullock C, Weingarten P, Zhou QY (Feb 2002). "Interaction of
gamma-COP with a transport motif in the D1 receptor C-terminus". Eur. J. Cell Biol. 81 (2):
77–85. doi:10.1078/0171-9335-00222. PMID 11893085.
27. ↑ Bermak JC, Li M, Bullock C, Zhou QY (May 2001). "Regulation of transport of the
dopamine D1 receptor by a new membrane-associated ER protein". Nat. Cell Biol. 3 (5):
492–8. doi:10.1038/35074561. PMID 11331877.
28. ↑ Jump up to:28.0 28.1 28.2 28.3 28.4 28.5 28.6 28.7 Nishi A, Kuroiwa M, Shuto T (July 2011). "Mechanisms for the
modulation of dopamine d(1) receptor signaling in striatal neurons". Front Neuroanat. 5:
43. doi:10.3389/fnana.2011.00043. PMC 3140648. PMID 21811441.
Dopamine D1 receptor hetero-oligomers
29. ↑ Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark
H, Soriano A, Barnes C, Goldberg SR, Lluis C, Fuxe K, Franco R (2008). "Identification of
dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions
in the striatum". J. Biol. Chem. 283 (38): 26016–
25. doi:10.1074/jbc.M710349200. PMC 2533781. PMID 18644790.
30. ↑ Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré
S, Lluís C, Franco R (2009). "Marked changes in signal transduction upon heteromerization of
 dopamine D1 and histamine H3 receptors". Br. J. Pharmacol. 157 (1): 64–75. doi:10.1111/j.1476-
5381.2009.00152.x. PMC 2697789. PMID 19413572.
31. ↑ Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O'Dowd BF (2008). "Mu-opioid
receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in
living cells". Eur. J. Pharmacol. 581 (3): 235–
43. doi:10.1016/j.ejphar.2007.11.060. PMID 18237729.
32. ↑ Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortés A, Lluís C,
Canela EI, Casadó V, McCormick PJ, Franco R (2016). "Heteroreceptor Complexes Formed
by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets
to Prevent Neuronal Death in Alzheimer's Disease". Mol. Neurobiol. doi:10.1007/s12035-016-
9995-y. PMID 27370794.

External links

 "Dopamine Receptors: D1". IUPHAR Database of Receptors and Ion Channels.

International Union of Basic and Clinical Pharmacology.
 Receptors,+Dopamine+D1 at the US National Library of Medicine Medical Subject
Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is
in the public domain.

e
Cell surface receptor: G protein-coupled receptors

e
Dopamine receptor modulators

Categories:

 CS1 maint: Uses authors parameter

 Genes on human chromosome
 Pages with broken file links
 Wikipedia articles incorporating text from the United States National Library of Medicine
 Dopamine receptors

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