Drugs acting on ANS

(Autonomic nervous system )

HIMANSHU N PANCHAL
Introduction to ANS
- Autonomic nervous system (ANS) represents - unconscious regulation and controls the visceral
function.
Neurotransmitter
Biosynthesis of neurotransmitter-
O
O Tyrosine
Phenylalanine HO HO O
OH hydroxylase
OH hydroxylase
NH2
NH2 HO HO NH2
Phenylalanine l-tyrosine l-dopa

L-aromatic amino
acid decarboxylase
Dopamine beta
OH phrnylethanolamine HO
hydroxylase HO
N-methyltransferase
N OH HO NH2
H HO NH2
OH OH
l-dopamine
Epinephrine Norepinephrine
Adrenergic receptors
- G-protein coupled receptors and classifi ed as α (alpha) and β (beta)
adrenoceptors.
- α- it is classified as α1 & α2. α1 act by the increasing the phospholipase C, D,
A2, & IP3/ DAG pathway- contraction of smooth muscle, genitourinary tracts,
and increase the secretions of glands and in the heart, it increases the force of
contraction
- α2 decresing in cyclic AMP, Ca+2 Ltype channels & increasing IP3/DAG.
decrease the insulin secretion, produces platelet aggregation, decreases the
release of NE as it has auto-regulation mechanism, and causes the vascular
smooth muscle contraction
Adrenergic receptors
β-RECEPTORS
The β receptors are further subdivided into three subtypes and distributed in the body, that is,
β1 (heart), β2 (bronchi, smooth muscles), and β3 (adipose tissue). Increses cAMP, & Ca+2 release &
causes secretion from glands, contraction of muscle.
Classification of drugs
I) based on the mode of action I) based on the mode of action
a). Direct acting c). Mixed acting agents
HO HO OH
OH
HO NH2
HO N HO NH2
H HN
OH OH
Adrenaline noradrenaline Ephedrin Metaraminol
b). Indirect acting
OH
H
NH2 N

HO
Methamphetamine Psudoephedrin
Chemical classification
A). α- agonist A). α- agonist
a). α1 agonist a). α1 agonist
i). Phenyl ethanolamine derivative ii). 2-arylimidazoline derivative
OH OH H
H N
HO NH2 HO N
N NH
N
Metaraminol Phenylepherin
Tetrahydrozolin Nephazolin
OCH3OH
NH2

OCH3
Methoxiamine
 Chemical classification
B). β agonists b). β2 agonist
a). β1 agonist i). Short acting β2 agonist
HO OH
HO

HO
HO NH2 N OH N
H
H OH
Dopamine OH
Metaproterenol Salburamol
OH HO N
H
HO N HO
N
H
HO OH
Dobutamine
Pirbuterol
Chemical classification
b). β2 agonist
ii). Long acting β2 agonist OH

O OH
N
H
OH
Salmeterol
OH
H H
H N N

O
HO OCH3
Formoterol
 m NH2
β
SAR of sympathomimetic p
α

A). Phenyl ring substitution m β- phenylethylamine

- substitution at m,p & α,β position of ethylamine side chain affect the activity & selectivity of
drug.
- -OH at m,p & beta ethylamine side chain (with favorable configuration) substitution- maximal
activity
- drug with catechol moiety- require for adrenergic receptor binding- other substituted phenyl
improve selectivity of drug towards receptor.
- replacement of catechol moiety with resorcinol gives metaproterenol, which is a selective β2-
receptor agonist.
- replacement of –OH of catechol with –CH3OH- salbutamol- a selective β2-receptor agonist.
- catechol has -OH at 3,4 position- poor oral activity- rapidly metabolize by COMT enzyme-
stubstiturtion at 3,5 position with -OH group- increases oral activity & resistance toward COMT.
SAR of sympathomimetic
B). Substitution at nitrogen
- important for direct activity.- Amine & ring should be separated by 2 carbon spacer.
- as substitution on N increases, α agonist activity decreases & β agonist activity. N-tertiary butyl
group enhances β2 selectivity.- size increases from hydrogen in noradrenaline to methyl in
adrenaline, isopropyl in isoproterenol, the activity of α receptor decreases and β receptor
increases.
HO HO

HO N HO NH2
H
OH OH
isoproterenol noradrenaline
- Primary and secondary amines are more potent direct-acting agonists than 3° or 4° amines.
SAR of sympathomimetic
iii). Substitution on the carbon side chain
- Methyl or ethyl substitution on the α-carbon-reduces the direct action on α & β receptor.
-α-alkyl group increases the duration of action of the phenyl ethylamine agonist by making the
compound resistant to metabolic deamination by MAO.
- α-substitution also significantly affects receptor selectivity.
- α-substitution is the introduction of a chiral center, which has pronounced effects on the
stereo-chemical requirements for activity.
 OH
H
HO N
Synthesis
1). Phenylepherine
Phenylepherin
- IUPACname- 3-(1-hydroxy-2-(methylamino)ethyl)phenol

OH
O O
H2/catalytic reduction HO
HO CH3NH2 HO
NH
Cl NH

2-chloro-1-(3-hydrox- 1-(3-hydroxyphenyl)-2 phenylepherine

yphenyl)ethan-1-one -(methylamino)ethan-1-one
 O O O
O Br KOH+ HO
AlCl3 BrF
+ Pd2(dba)3
Cl
O O 1-(3-hydroxy
benzene acetyl chloride acetophenone
phenyl)
O ethan-1-one
O O
CH3NH2 Br2 + AlCl3 O acetic anhydride
O Br
H2O Mg(ClO4)2
NaBH4 O O

3-acetylphenyl acetate
OH
H
HO N

Phenylepherin
 HO
2). Salbutamol HO
N
- IUPAC name- 4-(2-(tert-butylamino)-1-hydroxyethyl)-2 H
OH
-(hydroxymethyl)phenol
Salburamol

(NH2C(CH3)3)
HO O
HO 2-methylpropan-2-amine
+ Cl Cl
HO HO
Cl
2-(hydroxy 2-chloro
O
methyl)phenol acetyl chloride

HO MPV Reduction HO
aluminium isopropoxide
HO HO
N N
H H
OH O
Salbutamol
Classification of adrenergic antagonist
- non-selective α antagonists- - non-selective α antagonists-
A).beta halo alkyl amines B). Ergot alkaloid
N O
1) phenoxybenzamine H
HO
O O N R2
O
N
HN N O
Cl H R1
N
H
2) Dibenamine
Cl
N
Classification of adrenergic antagonist
- non-selective α antagonists- - non-selective α antagonists-
C). Imidazole derivatives D). Quinazoline derivatives
O
1) tolazoline N 1) prazosin O
N N O
N
N O
N
H
2). Phentolamine
H H 2N
N 2). Terazosin O
O
CH3 N O
N N
N
O
N
H2N
OH
Classification of adrenergic antagonist
- non-selective α antagonists- - non-selective α antagonists-
D). Quinazoline derivatives E). Miscellaneous
3). Doxazosin O 3). Chlorpromazine
O
N N O S
N
O
N O
H2N
Cl N
E). Miscellaneous
1) indoramine
N
H
N
N
HN O
 Classification of adrenergic antagonist
- β-receptor Blockers
A). β-Blockers with membrane stabilizing activity and intrinsic sympathomimetic property
1). Oxprenalol 2). metipranolol
O
H2C O N O N
HO H H
OH

B). Non-selective β blocker -

O
1). Propranolol (β-blockers with membrane stabilizing activity)
O

O N
H
OH
 Classification of adrenergic antagonist
C). β-blockers with cardio selective action (β1-blockers)
1) Betaxolol- 4). Atenolol
N HO
O H H
O N O O
OH
O 2). Esmolol NH2

O N 5). Metaprolol
O H HO
3). Bisoprolol OH H
N O
OH
O O
O O
N
H
Classification of adrenergic antagonist
D). Mixed α/β-adrenergic antagonists
1). Labetalol 2). Carvedilol

O
OH O N
H H
N OH
O
CH3
HO N
H
O NH2
 - SAR of β-adrenergic antagonist or
- SAR of propranolol
Replacement of -OH with –Cl HO N,N- disubstitution ses activity. &
retain Activity. maintained by sub. With phenyl ethyl,
HO hydroxyl phenyl ethyl, or methyl phenyl
N
Replacement of catechol H ethyl
ring with other ring can not OH
affect activity Replacement of Arometic ring with
other ring Determine pharmacokinetic
2 C chain essential for & Dynamic effects.
O N
activity H Bulky group like t-butyl, iso-propyl,
OH
are found in β blockers- secondary
Introduction of –OCH2 b/w β –OH produces chiral center- must amine must be there for optimal
aromatic ring & ethyl amine be in (S) configuration for optimal activity.
side chain provide antagonist activity- 100 time more potent then
activity (R) isomer
 Synthesis of propranolol O
OH
N
H
Propranolol
IUPAC Name- 1-(isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol

OH O O O N
H
OH
+ Cl O

Alpha- Naphthol Epichlorohydrin H2N Propranolol

Isopropyl amine
Cholinergic system
Biosynthesis of acetylcholine
SAR Of Anticholinergic agents