structure activity relationship (sar) adrenergic drugs · ppt file · web...

Structure activity relationship (SAR)of sympathomimetic amines, Adrenergic antagonist and Neurone blockers

DR. ISHOLA I.O. PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGYCMUL

INTRO

Phenylethylamine can viewed as parent compound, NA, AD, DA, ISOP posesss OH O-dihydroxybenzene known as catechol Directly acting sympathomimetic drugs influence both α and β receptors

SAR Separation of aromatic and amino group – greatest sympathomimetic activity occurs

when two carbon atoms separate the ring from amino group (DA, NA, AD etc) Substitution on the amino group- increase in the size of alkyl substituents increases

beta-receptor activity (isoprenaline) and vice versa, N-methylation increase the potency of primary amine

Substitution on the aromatic nucleus- maximal alpha and beta activity depends on the presence of hydroxyl groups on position 3 and 4. oH-on position 3 and 5 confers beta receptor selectivity on compounds with large amino substituents (terbutaline, metaproterenol- relax bronchial smooth muscle but less cardiac stimulation, when absent potency reduce

Compouns without one or both hydroxyl substituents are not acted upon by COMT and their oral effectiveness and duration of action prolonged

Methoxy substituents at 2 and 5 has highly selective alpha stimulating activity and large doses block beta-receptors

Albuterol is exempted

SAR Substitution on the alpha-carbon atom- this substitution block oxidation by MAO

(EPHEDRINE OR AMPHETAMINE), thus prolonging the duration of action Substitution on the beta-carbon atom- Substitution of a hydroxyl group on the

beta carbon generally decreases action within the CNS largely because it lowers lipid solubility but enhances agonist activity at both alpha and beta adrenergic receptor, ephedrine is less potent than methamphetamine as a central stimulant, it is more powerful in dilating bronchioles and increasing BP and HR

Optical isomerism- substitution on either alpha or beta carbon yields optical isomers Levo-substitution on beta-carbon confers the greater peripheral activity; L-ADR and L-

NA are 10X AS POTENT as their unnatural D-isomers; D-sub on alpha = more potent compound- D-AMP more potent than L-amp in central but not peripheral

SAR

ADRENERGIC RECEPTOR ANTAGONIST

Drugs interfere with function of the SNS and thus profound effects on the physiology of sympathetically innervated organs

Adrenergic antagonist inhibit the interaction of NA,AD, and other sympathomimetic drugs with adrenergic receptors

All the ADR antagonists bind competitively except phenoxybenzamine (covelent)

Alpha adrenergic antagonists

α1 mediate the contraction of arterial and venous smooth muscle α2 involved in suppressing sympathetic output, increasing vagal

tone, facilitate platelet aggregation and inhibit the release of NA and Ach from nerve endings and regulate metabolic effects

Blockade of α1 receptors inhibit vasocontraiction = vasodilation in both arterial and veins = decrease in PVR = fall in BP (opposed by baroreceptor reflexes)

Activity less in supine than upright position

Cont’d

α2 control peripheral and central Activation of α2 inhibit the release of NA from

Psympathetic nerve endings Blockade of α2 increase SNS outflow and

potentiate the release of NA from nerve endings leading to activation of α1 and B1 receptors in the heart

Adrenergic receptor agonist/antagonist

Adrenergic agonist/antagonist

Adrenergic System

ALPHA BLOCKERS:Non-selective Phenoxybenzamine, Phentolamine

Alpha -1 selective Prazosin, Terazosin, Tamsulosin

Alpha-2 selective Yohimbine

Adrenergic System

BETA BLOCKERS:

Non selective : Propranolol, Nadolol, Timolol With Partial agonist : PindololBeta 1 selective : Atenolol, MetoprololBeta and alpha 1 blocker : Labetolol, Carvedilol

Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible

NH3

COOH

Gq

Phospho-lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Receptor agonists activate signal transduction pathways

a1 adrenergic receptor

HO

HO CH

OH

CH2 NH2

Norepinephrine

Receptor antagonists block agonist binding to the receptor

NH3

COOH

Gq

Phospho-lipase C

Antagonist

HO

HO CH

OH

CH2 NH2

Norepinephrine

What effect would an antagonist alone have on receptor activation?

Clinical pharmacology of a-adrenergic receptor antagonists

Drug ReceptorRoute ofadmin. Clinical uses

Side effects of a1 receptor antagonists:

Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

Phenoxybenzamine a1, a2 Oral Pheochromocytoma, hypertensive crisisPhentolamine a1, a2 Parenteral Pheochromocytoma, hypertensive crisis,

male impotencePrazosin a1 Oral Hypertension, benign prostatic

hypertrophyTerazosin a1 Oral Hypertension, benign prostatic

hypertrophyDoxazosin a1 Oral Hypertension, benign prostatic

hypertrophy

Non-selective adrenergic receptor antagonistsb-Haloalkylamines

N CH2 CH2 XR

RR= aromatic, alkylX= Cl-, Br-, etc.

b-Haloalkylamines

NO

CH3

Cl

Phenoxybenzamine (Dibenzyline)

Non-selective a receptor antagonist

Also blocks acetylcholine, histamine, and serotonin receptors

Irreversible antagonist resulting from covalent modification of receptor

Non-selective adrenergic receptor antagonists

b-Haloalkylamines: Mechanism of receptor inactivation

receptor alkylatedreceptor

N

Cl

R RN

R R Cl-

Aziridinium ion

NR R Cl-

Nu

NR R

Nu

Non-selective adrenergic receptor antagonists

Imidazolines

Phentolamine (Regitine)

Non-selective a receptor antagonist

Competitive (reversible) blocker

Potent vasodilator, but induces pronouced reflex tachycardia

Block of presynaptic a2 receptors may promote release of NE

Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist

Non-selective adrenergic receptor antagonists

N

NH

N

HO

H3C

CH2

Reversible vs. Irreversible receptor blockade

-10 -8 -6 -40

50

100

Log [Norepinephrine]

a1 A

dren

ergi

cre

cept

or a

ctiv

atio

n

-10 -8 -6 -40

50

100

Log [Norepinephrine]

a1 A

dren

ergi

cre

cept

or a

ctiv

atio

n1 M Phent

+ Phentolamine + Phenoxybenzamine

10 M Phent

1 M Phenox

10 M Phenox

a1-adrenergic receptor antagonists “Quinazolines” Vary in half-life:

Prazosin 3 hrs Terazosin 12 hrs Doxazosin 20 hrs

Undergo extensive metabolism, excreted mainly in the bile

Vasodilators Relaxation of smooth muscle in enlarged

prostate and in bladder base “First-dose” effect

N

NH3CO

H3CONH2

N

N R

O

O

OO

O

Prazosin: R =

Terazosin: R =

Doxazosin: R =

Quinazoline ring

Piperazine ring

Acylmoiety

(Minipres)

(Hytrin)

(Cardura)

Other a adrenergic receptor antagonistsErgot alkaloids

N

N

O

R'O

R

O NH

O NCH3

NH

Derivatives of Lysergic Acid Product of the grain fungus

Claviceps purpura 5 Major alkaloids based on R

and R’; Ergotamine the most common

Used in the treatment of migraine

Ergots possess strong oxytocic action

a2-adrenergic receptor antagonists

Yohimbine (Yocon)

Indole alkaloid Found in Rubaceae and

related trees. Also in Rauwolfia Serpentina.

Blockade of a2 receptors increases sympathetic discharge

Folklore suggests use in the treatment of male impotence

NH

N

H

H

H3CO2C

H

OH

b-adrenergic receptor antagonists

Ar

O NH R

OH

Ar = aromatic ring structure

R = bulky alkyl group (isopropyl or tert-butyl)

AryloxypropanolaminesNote: non-carbon atomin side chain

b-adrenergic receptor antagonists

Non-selective Lipophilic Local anesthetic

properties Blockade is activity-

dependentPropranolol(Inderal)

O NH

OH

CHCH3

CH3

b-adrenergic receptor antagonistsPharmacological effects Decreased cardiac output and heart

rate Reduced renin release Increase VLDL, Decrease HDL Inhibit lipolysis Inhibit compensatory

glycogenolysis and glucose release in response to hypoglycemia

Increase bronchial airway resistance

Propranolol(Inderal)

Therapeutic uses for b-adrenergic receptor antagonists:Hypertension, angina, cardiac arrhythmias, migraine, stage fright,

thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

O NH

OH

CHCH3

CH3

Non-selective b-adrenergic receptor antagonists

Thiadiazole nucleus with morpholine ring

Administered: Oral, Ophthalmic Uses: Hypertension, angina,

migraine, glaucoma

O NH

OH

C

CH3

CH3

CH3

N S

NNO

Timolol (Timoptic, Blocadren)

O NH

OH

CHCH3

CH3HO

HONadolol (Corgard)

Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in

urine Administered: Oral Uses: Hypertension, angina,

migraine

How will b-blockers affectpupil size?

Non-selective b-adrenergic receptor antagonists

Pindolol (Visken)

Possesses “Intrinsic sympathomimetic activity (ISA)

Partial agonist Less likely to cause bradycardia

and lipid abnormalities Administered: Oral Uses: Hypertension, angina,

migraine

O NH

OH

CHCH3

CH3

NH

What would a pindolol dose-response curve look like?

Non-selective b-adrenergic receptor antagonists

Possesses “Intrinsic sympathomimetic activity (ISA)

Partial agonist Less likely to cause bradycardia

and lipid abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma

Carteolol (Cartrol, Ocupress)

NH

O

O NHOH

CCH3

CH3

CH3

Selective b1-adrenergic receptor antagonists

“Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina,

antiarrhythmic, congestive heart failure

R

OHO N

HCH

CH3

CH3

Metoprolol (Lopressor, Toprol)R= CH2

Bisoprolol (Zebeta)R= O

O CH3

CH2CH2

OCH

CH3

CH3

Selective b1-adrenergic receptor antagonists

Atenolol (Tenormin)

“Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina

O NH

OH

CHCH3

CH3

NH2

O

Selective b1-adrenergic receptor antagonists

Esmolol (Brevibloc)

Very short acting Half-life: 9 minutes Rapid hydrolysis by esterases

found in red blood cells Administered: Parenteral

Note: incompatible with sodium bicarbonate

Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension

O NH

OH

CHCH3

CH3

OCH3

O

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms

of hypoglycemia, withdrawal syndrome

Action Potential

Na+

Effect of chronic b-receptor blockade

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

Action Potential

Na+

Effect of chronic b-receptor blockade: Receptor up-regulation

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms

of hypoglycemia, withdrawal syndrome

Contraindications: Asthma, COPD, congestive heart failure (Type IV)

Mixed adrenergic receptor antagonists

Labetalol (Normodyne, Trandate)

Non-selective b receptor antagonist

a1 receptor antagonist Two asymmetric carbons (1 and

1’) (1R, 1’R)-isomer possesses b-

blocking activity (1S, 1’R)-isomer possesses

greatest a1 receptor blocking activity

b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists

Administered: Oral, parenteral Uses: Hypertension,

hypertensive crisis

HN

OH

CH3HO

CONH2

11'

Mixed adrenergic receptor antagonists

Carvedilol (Coreg)

Non-selective b receptor antagonist a1 receptor antagonist Both enantiomers antagonize a1

receptors Only (S)-enantiomer possesses b-

blocking activity

OCH3

ONH

O

OH

NH

b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists

Administered: Oral Uses: Hypertension, congestive

heart failure (Types II and III)

Action Potential

Na+

Pharmacologic manipulation of the adrenergic system

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

b

NE

MAO

12

3

Inhibition of norepinephrine synthesis

HO CH2 CH NH2

HO

HO CH

OH

CH2 NH

CH3

HO

HO CH

OH

CH2 NH2

COOH

HO CH2 CH NH2

COOH

HO

HO

HO CH2 CH2 NH2

TYROSINE

DOPA

DOPAMINE

NOREPINEPHRINE

EPINEPHRINE

tyrosine hydroxylase

aromatic L-amino acid decarboxylase

dopamine b-hydroxylase

phenylethanolamine-N-methyltransferase

MetyrosineX

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

b

NE

MAO

ReserpineGuanethidine

GuanethidineGuanethidine,Bretylium

Catecholamine depleters

Slow onset of action Sustained effect (weeks) Used in the treatment of

hypertension May precipitate depression

NH

N

H3CO2C

H3CO

H

H

H

OC

OCH3

OOCH3

OCH3

OCH3Reserpine (Serpasil)

Indole alkaloid obtained from the root of Rauwolfia serpentina

Block vesicular monoamine transporters

Deplete vesicular pool of NE

Drugs that reduce storage or release of NE

Possess guanidino moiety (pKa > 12) Resonance stabilization of cation “spreads”

positive charge over the entire four atom system Almost completely protonated at physiological

pH “Pharmacologic sympathectomy” Effects can be blocked by transport blockers Uses: Hypertension

Guanethidine (Ismelin)

N

HN

CNH2

NH

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

b

NE

MAO

Guanethidine

GuanethidineGuanethidine,

Drugs that reduce storage or release of NE

Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent further

release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular fibrillation)

Bretylium tosylate (Bretylol)Br

CH N

CH3

CH3

CH2CH3 CH3O3S

OBRIGADO