Medicinal chemistry -l-Second year-Fourth semester - Lecture Vll adrenergic antagonists.

1. Medicinal chemistry l
Lecture VIl
Adrenergic blockers /Antagonists
By Manjusha SK
Associate professor

2. Introduction
 Introduction-
These are the drugs which block the effects produced by Sympathomimetic drugs. These are classified on
the basis of their site of action as follow,
1.Alpha (a) Adrenergic Blockers : The drugs antagonises the effects produced by the drugs acting on a-
receptors
2.Beta (β) adrenergic blockers : The drugs antagonises the effects produced by the drugs acting on β -
receptors

3. 1.Alpha (a) Adrenergic Blockers classification

4. 1.Alpha (a) Adrenergic Blockers
 Non-selective a-adrenergic antagonist –Haloalkylamines
 1. Phenoxybenzamine –
 Mechanism of action –It is an irreversible alpha blocker and it blocks both alpha 1 and alpha 2
receptors.
 Uses –Used in the treatment of hypertension.
Used in the treatment of urinary retension.
 Imidazolines – Pentolamine and Tolazoline
 1.Tolazoline -

5. 1.Tolazoline -
 Synthesis –
 Mechanism of action - It is a competitive inhibitor of a-receptor. Its structure is similar to that of
alpha agonist, so it bind reversibly with the alpha receptors and block the effects of a-
receptors.
 Uses - It is used in persistent pulmonary hypertension in new born.
- It is used as vasodilator.
- It is used to antagonize the overdoses of clonidine.
 a1selective antagonist : It has affinity for al-receptors which is 1000 times more than that for
a2-receptors.

6. a1selective antagonist 1.Prazosin-
 Structure-
 Uses - It is used in the management of hypertension and in the treatment of heart failure and
Raynauds syndrome(a disease characterized by spasm of the arteries).
 Hydrogenated ergot alkaloids –
 Dihydroergotamine-
 Mechanism of action - It is an antagonist of a-adrenergic receptors.
 Uses -It is used in the treatment of migraine, medication overdose headache.
It is also used as a vasoconstrictor.

7. 2.Beta (β) adrenergic blockers
 The drugs antagonises the effects produced by the drugs(catecholamines) acting on β –receptors.
 These are futher classified into,
1.ß1 selective
2. ß2 selective
3. Non selective
 SAR of ß blockers – IT again divided into two class according to its structure,
1. Aryl ethanolamines 2. Aryloxy propanolamines
 SAR of Aryl ethanolamines –
 Basic drug in this category is Isoproterenol
1.Phenolic OH group is important for agonist activity.
2.Two carbon chain must be there for its activity, it should not more or not less.
3.Phenylethyl,hydroxy phenylethyl groups added to N for ß blocker activity.
4.Cyclic alky substitution provides better activity at N atom.
5. Two OH group attached to phenyl ring replaced by methyl sulphonamide increases activity.

8. SAR of Aryloxy propanolamines
 Basic drug in this category is Propranolol
 Structure –
1.The -OCH2 group is placed between
the aromatic ring and the
ethanolamino side chain ,which is important for its activity.
2. Most of the derivatives have substituted phenyl rings in place of naphthyl ring for
its better activity.
3. Alkenyl and alkenyloxy groups when present in the ortho positions on phenyl ring
gives good ß-antagonist activity.
4. Substitution of —CH3 —OCH3, —NO2 groups on the phenyl ring generally done at
2 and 3 position for its better activity.
5.Isopropyl and t-butyl groups present on the amino group provides nucleophilicity to
the amino group, hence most favoured

9. Some of the ß-blockers are
 1) Propranolol-
 Structure –
 Mechanism of action : It is a non-cardioselective ß-adrenergic blocker.
Its mechanism of action may be due to-Decreased renin release, Reduced
cardiac output and Decreased peripheral resistance.
 Synthesis – The a- napthol treated with epichlorohydrin in presence of base,
the intermediate the treated with isopropylamine.
 Uses - It is used in the treatment of hypertension and in cardiac arrythmias.

10. 2)Atenolol
 Structure –
 Mechanism of action - Atenolol belongs to a class of drugs known as beta blockers. It works
by blocking the action of certain natural chemicals in your body, such as epinephrine, on the heart
and blood vessels.
 Uses - It is used in the management of hypertension, angina pectoris and for the management of
symptoms of alcohol withdrawal.
It is also given in the emergency treatment of cardiac arrythmias.
3) Betaxolol –
 Structure –

11. 3) Betaxolol -
 Mechanism of action - Betaxolol selectively blocks catecholamine stimulation of beta(1)-
adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart
rate, cardiac output, systolic and diastolic blood pressure.
 Uses - It is used in the treatment of hypertension and in the management of glaucoma.
 4) Esmolol –
 Structure –
 Mechanism of action - It works by blocking beta-adrenergic receptors in the heart, which leads to
decreased force and rate of heart contractions.
 Uses - It is used in the treatment of supraventricular tachycardia
(is as an irregularly fast or erratic heartbeat)
It is used in the management of atrial fibrillation
(is an irregular and often very rapid heart rhythm that can lead to blood
clots in the heart).

12. 5) Labetalol
 Structure –
 Mechanism of action - Labetalol is a non-cardioselective ß-blocker and acts as a competitive blocker
on both –a and ß-receptors. It works by relaxing blood vessels and slowing heart rate to improve
blood flow and decrease blood pressure.
 Uses - It is given orally in the treatment of hypertension.
It is given intravenously in the treatment of severe hypertension.
6) Carvedilol –
 Structure –
 Uses - It is used in the management of congestive heart failure, and in hypertension also.

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