Adrenergic agents - Biosynthesis of adrenaline, Effects of the neurotransmitter and SAR of sympathomimetic drugs

Adrenergic agents

Intended learning outcomes

At the end of the lecture students will be able to

• Classify the nervous system

• Understand the biosynthesis of adrenaline

• Predict the metabolic products of adrenaline

• Describe the effects of the neurotransmitter on the various receptors

• Definition of sympathomimetic drugs

• SAR of sympathomimetic drugs

Divisions of human nervous system

Human Nervous system

1. Central Nervous System

2. Peripheral Nervous System

- Autonomic Nervous System

Peripheral Nervous System

Peripheral Nervous System - Includes neurons and ganglia outside of the brain and spinal cord

1. *Autonomic Nervous System (involuntary) *Either “fight and flight” mode or “rest and digest”

2. Somatic Nervous System (voluntary)

- Sympathetic Nervous System (adrenergic)

- Parasympathetic Nervous System (cholinergic)


Adrenergic nervous system:

• Adrenergic nervous system is a group of organs and nerves in which adrenaline and/or noradrenaline are released as neurotransmitters

• Adrenergic nerve release neurotransmitters: noradrenaline, adrenaline, dopamine and produce their effect

Adrenergic transmission


• Natural: Adrenaline, Noradrenaline, Dopamine

• Synthetic: Isoprenaline, Dobutamine

• Non-Catecholamines:– Ephedrine, Amphetamines, Phenylepherine, Methoxamine, Mephentermine

• Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group

• Noradrenaline/ norepinephrine: It is transmitter at postganglionic sympathetic sites (except sweat glands, hair follicles and some vasodilator fibres)

• Adrenaline/Epinephrine: It is secreted by adrenal medulla and may have a transmitter role in the brain

• Dopamine: it is a major transmitter in basal ganglia, limibic system, CTZ, anterior pituitary, etc

Biosynthesis of Catecholamine

• NE is synthesized, stored and released in the synaptic vessels of the sympathetic neurons.

• Adrenaline is synthesized and stored in the adrenal medulla and released only in emergency conditions.

Step 1:

• L-Tyrosine is transported actively into the adrenergic neuron, where it is 3’-hydroxylated by tyrosine hydroxylase (TH, tyrosine -3-monooxygenase).

• L-DOPA = dihydroxyphenylalanine.

• Enzyme requires molecular O2, Fe2+, and a tetrahydropteridine cofactor.

• Enzyme follows end-product inhibition, feedback inhibition.

Step 2:

• Decarboxylation of L-DOPA to give DA by enzyme DOPA decarboxylase (L-aromatic amino acid decarboxylase).

Step 3:

• DA is actively transported into storage vesicles by vesicular monoamine transporter (VMAT).

• Side-chain hydroxylation of DA gives NE by dopamine β -hydroxylase (DBH, dopamine β -monooxygenase).

Step 4:

• N-methylation of NE to give E in the adrenal medulla by phenylethanolamine-N-methyltransferase (PNMT).

• PNMT is a cytosolic enzyme and the methyl donor S-adenosyl methionine (SAM) is required for the N-methylation of NE.

Metabolism of Catecholamine

• These metabolites are conjugated with glucuronides and sulphates and gets eliminated

Adrenergic receptors

Adrenergic Receptor Subtypes

• Are membrane-associated G-protein-coupled receptors.

• G-protein = Guanine nucleotide-binding proteins.

• In 1948, Ahlquist proposed and designated α- and β- adrenoceptors based on their apparent drug sensitivity.

• Further division of adrenoceptors α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, β3.

Imidazolines show high affinity toward α2-adr. Receptor, thus is also called imidazoline receptor.

Sympathomimetic agents

• Compounds that produce effects similar to stimulation of sympathetic nervous system activity are known as sympathomimetic.

Synonyms: Adrenergic Stimulants

Act by: stimulating adrenergic receptors or affect the life cycle of adrenergic neurotransmitters.

SAR of Sympathomimetic agents

• The common structural features required for adrenergic agents are asubstituted benzene ring and a primary or secondary aliphatic aminogroup separated by 2 carbon atoms from benzene ring.

• The agent in this class have a hydroxyl group on the β-carbonatom of the side chain.

• Hydroxy substituted carbon must be in R absolute configurationfor maximum direct activity.

Substitution on the amino group

• The receptor selectivity depends on the size of the alkyl group present on the nitrogen atom.

• Increase in the size from hydrogen in nor-adrenaline to isoproterenol decreases activity at α-receptor and increases activity at β-receptor.

• Substitution of amino group with a tertiary butyl group also provide selectivity for different β receptors.

e.g.  Terbutaline is a selective β2 agonist whereas, isoprenaline is a non-selective β agonist.


Substitution on the α-carbon atom in the side chain

• Small alkyl groups like methyl or ethyl may be present on the- carbon atom.  Such substitution slow the metabolism carried out by Mono amine oxidase.

• An ethyl group in this position diminish α-activity and afford compound having β activity.

• Substitution on this carbon introduce another asymmetric center producing pairs of diastereomers, which can have significantly different biological activity.

• e.g. maximum direct activity in streoisomer of α-methyl nor- epinephrine reside with the streoisomer having 1R, 2S absolute configuration. While 1R, 2R streoisomer is indirectly activity.

Substitution on the aromatic ring

• Compound having both 3,4-dihydroxy group on benzene ring are active at both α and β receptors and they rapidly metabolize COMT.

• Change in substitution pattern to 3,5-dihydroxy as in terbutaline gives good oral activity and selectivity for β2 receptor.



• Adrenaline or epinephrine is the neurotransmitter of the adrenergic nervous system

• It is also called as the sympathetic nervous system

– It comes under the autonomic nervous system

• It is synthesized in the body from the amino acid tyrosine

• It is metabolized by MAO and COMT, and finally eliminated after conjugation with gluconoride

• The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3.

Post a Comment