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)

Neurotransmission

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

Catecholamine:

• 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.

Terbutaline

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.

Terbutaline

Summary

• 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.

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