Drugs acting on Autonomic Nervous System (Sympathomimetic agents & Adrenergic Antagonists) || B.PHARM SEMESTER IV (2nd Year 2nd Sem.) || Unit-2 || Medicinal Chemistry-I

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The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body.

The Central nervous system is made up of the brain and spinal cord and The Peripheral nervous system is made up of the Somatic and the Autonomic nervous systems.

Adrenergic Neurotransmitters are 3 types

Collectively called catecholamines

1. Noradrenaline (NA) - at postganglionic sympathetic sites (except sweat glands, hair follicles) & in certain areas of brain.

2. Adrenaline (Adr) - secreted by adrenal medulla

3. Dopamine (DA) - transmitter in basal ganglia, limbic system, CTZ, anterior pituitary.

Biosynthesis of Catecholamine

Steps in the synthesis of Catecholamines (CAs)

- Synthesis of CAs

- Storage of CAs

- Release of CAs

- Uptake of CAs

- Metabolism of CAs

All belong to super family of G-protein-coupled receptors.

Adrenergic receptors are classified into two types

Sympathomimetic drugs / Adrenergic Agonist

Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and norepinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction.

Sympathomimetic agents that partially or completely mimic the actions of norepinephrine (NE) or Epinephrine (Epi).

They are also called as Sympathomimetic drugs / Adrenomimetic Drugs / Adrenergic Agonist / Adrenoreceptor Agonists

Classification of Sympathomimetic Drugs:

They are chemically classified into two main categories
A) Catecholamines
B) Non-catecholamines

SAR of Adrenergic Agonists / β-phenylethylamines / Sympathomimetic Agents/ Arylethanolamines
1. Structure required for Activity

a) Phenyl Ethylamine as parent compound

b) Catechol or Aromatic Ring

c) β-carbon hydroxy & amino terminal

Replacement of meta hydroxyl of catechol increases β2 selectivity and decreases metabolism by COMT.

Removal of para hydroxyl group from epinephrine produce selective α1 agonist.

Substitution at nitrogen

The nature of amino substituent determines α / β receptor selectivity.

As the size of alkyl group on nitrogen increases, activity at α-receptor decreases and activity at β -receptor increases.

Synthesis of Phenylephrine:

Synthesis of Salbutamol:

Therapeutic Uses of Sympathomimetic Agents:

A – Anaphylactic Shock – Exp: Epinephrine

B – Bronchial Asthma – Exp: Salbutamol, Terbutaline, Isoprenaline, Epinephrine

C – Cardiogenic shock – Exp: Dobutamine / Cardiac Arrest - Exp: Epinephrine

D – Delay of Parturition – Exp: Terbutaline, Ritodrine / Delay absorption of Local Anesthetics – Exp: Adrenaline

H – Hypertension – Exp: Clonidine

M – Migraine – Exp: Clonidine

N – Used as CNS stimulant in Narcolepsy – Exp: Amphetamine

N – Nasal Decongestion – Exp: Ephedrine, Phenylephrine, Methoxamine

P – Premature labor – Exp: Salbutamol

Sympatholytic drugs / Adrenergic Antagonist

The agents which antagonise the action of Sympathomimetic agents or sympathetic stimulations are called Sympatholytic agents.

Alpha adrenergic blockers / Alpha Antagonists

Alpha & Beta Antagonists are prevent the interaction of endogenous neurotransmitter NE or Sympathomimetics with corresponding adrenergic receptors.

Bind specifically to alpha receptors and interfere with catecholamine and Sympathomimetic action.

Role of Alpha-1 & Alpha-2 Antagonists

Alpha-1:

- Vasoconstriction

- Increased peripheral resistance

- Increased blood pressure

Alpha-2:

- Inhibition of Norepinephrine release

- Inhibition of insulin release

Classification of Alpha Blockers:

Structures of Alpha Blockers

Synthesis of Tolazoline:

Therapeutic Uses of Alpha-Adrenergic Blockers:

Hypertension - alpha-1 selective

• Pheochromocytoma (Conditions associated with increased sympathetic activity)

• Hemodynamic shock

• Peripheral vascular disease – Raynaud’s

• Congestive heart failure (CHF)

• Benign prostatic hyperplasia (BPH)

• Pulmonary hypertension – tolazoline

Beta adrenergic blockers / Beta Antagonists

Bind selectively to beta receptors

Interfere with ability of catecholamines or Sympathomimetics to

provoke beta receptors (heart, smooth muscle of airway and blood vessel).

Propranolol is standard beta antagonist drug to which all beta

antagonists are compared.

Role of Beta-1 & Beta-2 Antagonists

Beta-1:

- Tachycardia

- Increased lipolysis

- Increased myocardial contractility

Beta-2:

- Vasodilation

- Bronchodilation

Classification of Beta Blockers:

Structures for Beta Blockers:

Synthesis of Propranolol:

SAR of Beta Blockers / Adrenergic Antagonists / Sympatholytic Agents/ Aryloxy Propanolamines

1. OCH₂ group is placed between the aromatic ring and ethanolamino side chain, which is essential for the activity.

2. The hydroxyl bearing carbon of the aryloxy prpanolamine side chain play critical role in the interaction of β-antagonist drugs with β-receptor.

3. Alkyl Amino group is must be a secondary amine for optimal activity.

4. Isopropyl and t-butyl groups present on the amino group provides nucleophilicity to the amino group. E.g: Atenolol

5. The two carbon chains are essential for activity.

6. N, N-disubstitution decreases the beta blocking activity.

7. The aromatic ring and it substituent is the primary determinant of β1 antagonist activity.

8. Alkenyl groups present in the ortho position on aryl ring gives good beta antagonist activity. E.g: Oxprenolol, Alprenolol

9. Most of the derivatives have different aryl group like Phenyl, Naphthalene & Indole. E.g: Atenolol, Propranolol & Pindolol

Therapeutic Uses of Beta-Adrenergic Blockers:

Note: All information copyright @ www.pharmawisdom.co.in

Prepared By:
S.Seetaramswamy
Assoc. Prof.
Dept. Pharmaceutical Chemistry

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