The document discusses adrenergic receptors and agonists. It begins by introducing the adrenergic system and sympathetic nervous system responses. It then describes the different types of adrenergic receptors (α1, α2, β1, β2, β3), their locations, functions and selective agonists/antagonists. The mechanisms of action, indications, and structures of various adrenergic agonists are outlined. The document concludes by discussing structure-activity relationships of adrenergic agonists and providing examples of syntheses of newer agonists like bitolterol and brimonidine.

1. Presented by:
Mohd Shafeeque
M. Pharm. 1st Sem.
(Pharm. Chemistry)
Jamia Hamdard

2. CONTENTS:
 INTRODUCTION
 ARENERGIC RECEPTORS
 CLASSIFICATION
 MECHANISM OF ACTION
 INDICATIONS
 STRUCTURE ACTIVITY RELATIONSHIP
 SYNTHESIS OF NEWER ADRENERGIC
AGONISTS

3. INTRODUCTION:
 Adrenergic system is an evolutionarily ancient defence
system, which consists of the organs and nerves in
which catecholamines, noradrenaline (norepinephrine) or
adrenaline (epinephrine) act as neurotransmitter or
neurohormone.
 The substances that produce effects similar to stimulation
of sympathetic nervous activity are known as
sympathomimetics or adrenergic stimulants.
 In general, stimulation of sympathetic nervous system
causes what is known as a “fight-or-flight” responses.
These effects include an increased rate and force of
heart contraction, a rise in blood pressure, a shift of blood
flow to skeletal muscles, dilation of bronchioles and
pupils and an increase in blood glucose levels through
gluconeogenesis and glycogenolysis.

4. BIOSYNTHESIS, STORAGE, RELEASE, REUPTAKE AND
METABOLISM OF NOREPINEPHRINE:
1. Synthesis of NE
 Hydroxylation of tyrosine is the rate-limiting step.
2. Uptake into storage vesicles
 Dopamine enters in vesicle and converted to NE.
 NE is protected from degradation in the vesicles.
 Transport into the vesicle is inhibited by reserpine
3. Release of neurotransmitter
 Influx of calcium ion causes fusion of the vesicle with the cell
membrane in a process known as exocytosis.
 Release is blocked by Guanethidine and Bretylium.
4. Binding to receptor
 Post synaptic receptor is activated by the binding of
neurotransmitter.
5. Removal of NE
 Released NE is rapidly taken into the neurons.
 Reuptake is inhibited by Cocaine and Imipramine
6. Metabolism
 NE is methylated by COMT and oxidized by MAO

5. BIOSYNTHESIS, STORAGE, RELEASE, REUPTAKE
AND METABOLISM OF NOREPINEPHRINE:

6. ADRENERGIC RECEPTORS OR
ADRENOCEPTORS:
TYPES OF
ADRENOCEPT
-ORS
α
α1 α2
β
β1 β2 β3
❖All adrenergic receptors are GPCR:

7. Differences between α1 & α2 receptors:
α1 α2
Location
and function
Postjuntional on effector
organs
Blood vessels-
Contraction
Uterus- Contraction
Gland- Secretion
Gut- Relaxation
Heart- Arrythmia(at higher
dose)
Prejunctional on nerve ending,
also postjunctional in brain,
pancreatic beta cells and
extrajunctional in certain blood
vessels, platelets
Inhibition of transmitter release
Vasoconstriction
Decreased central sympathetic
flow
Decreased insulin release
Platelet aggregation
Selective
agonist
Phenylephrine,
Methoxamine
Clonidine
Selective
antagonist
Prazosin Yohimbine, Rauwolscine
Effector
pathway
IP3/DAG ↑, Phospholipase
A2 ↑- PG release
cAMP↓ , K+ channel ↑, Ca++
channel ↑ or ↓ , IP3/DAG ↑

8. Differences between β1, β2 & β3 receptors:
β1 β2 β3
Location
and
functions
Heart- Cardiac
stimulation: increase
rate, force &
conducting velocity
JG Cells of kidney-
release renin
Bronchi- dilation
Blood vessels-
dilation of
arteriole & veins
: fall in BP
Uterus-
relaxation
Urinary tract-
relaxation
Eye- enhance
aqueous
secretion
Adipose tissue-
lipolysis:
increase in free
fatty acid
Selective
agonist
Dobutamine Salbutamol,
Terbutalin
Mirabegron
Selective
antagonist
Metoprolol, Atenolol α-methyl
propranolol
Effector
pathway
cAMP ↑ , Ca++ channel ↑

9. Classificationof Adrenergic Drugs:
Selective α - Adrenergic
Agonists
Selective β -Adrenergic
Agonists
Mixed Acting
Sympathomimetics
(a)α1 – Agonists
❖ Phenylethanolamines:
▪ Metaraminol
▪ Methoxamine
▪ Phenylephrine
❖ 2-Arylimidazoline:
▪ Naphazoline
▪ Oxymetazoline
▪ tetrahydrozoline
(a)β1- Agonists
❖ Catecholamines:
▪ Dopamine
❖ Arylalkyl derivative:
▪ Dobutamine
❖ Phenylpropylamines:
▪ Ephedrine
▪ Pseudoephedrine
❖ Phenylisopropylamin-
es:
▪ Amphetamine
▪ Methamphetami
-ne
(b) α2- agonists
❖ 2-Aminoimidazolines:
▪ Clonidine
▪ Brimonidine
▪ Apraclonidine
(b) β2- Agonists
❖ Catechol derivatives:
▪ Albuterol
▪ Solmetrol
❖ Acid-ester derivatives:
▪ Colterol

10. STRUCTURES:
N
H
CH3
OH
H
O
H
NH
N
CH3
CH3
C
H3
CH3
C
H3
O
H
N
H
CH3
OH
CH3
NH
N
Cl
Cl
N
H
OH
H C
H3
CH3
CH3
O
H
O
H
NH2
CH3
Epinephrine
Oxymetazoline
Ephedrine
Clonidine Dopamine
Albuterol Amphetamine
NH2
O
H
O
H
Phenylephrine
Norepinephrine
N
OH
O
H
O
H
CH3
H OH
O
H
O
H
NH2

11. MECHANISM OF ACTION OF ADRENERGICAGONISTS:
❖ Direct-actingagonists:
✓ Produce their effect by directly stimulating the receptor
site.
✓ Epinephrine, Norepinephrine, Isoproterenol, Dopamine
❖ Indirect-actingagonists:
✓ Release endogenous norepinephrine which then
stimulates the receptor
✓ Amphetamine & Tyramine
❖ Mixed-actionagonists:
✓ Either directly stimulate the receptor or release
endogenous NE
✓ Ephedrine & Metaraminol

12. INDICATION OF ADRENERGIC DRUGS:
 Heart block, cardiac arrest
 Treatment of asthama. Eg. Salbutamol
 Treatment of Hypertension.
 Used for prolongation of local anaesthetic action by
vasoconstriction. Eg. Adrenaline
 To control local bleeding. Eg. Adrenaline
 As nasal decongestant. Eg. Oxymetazoline
 In acute hypotension. Eg. Norepinephrine
 Inhibition of uterine contraction. Eg. Nylidrine

13. SAR OF ADRENERGIC AGONIST:
Str. Requirement for activity:
✓N- primary or secondary
✓2- Carbon between substituted
benzene & amine grp
✓A Hydroxyl grp β to amine is
essential for adrenergic
agonistic activity
R1- substitutionon N:
❖With alkyl grp greater than methyl decreases alpha receptor activity &
increases beta receptor activity. Eg. Adrenaline(methyl) have more affinity
for alpha Isoprenaline(isopropyl) have more affinity for beta
❖With tertiary butyl group : becomes β2 selective :eg. Colterol
❖Substitution with larger lipophilic groups : have alpha blocking activity eg.
Labetalol
1'
6'
2'
5'
3'
4'
β
α N
H
R
1
OH
R
2
R3

14. SAR OF ADRENERGIC AGONIST:
❖Substitution over R2 :
 The substitution over alpha carbon to amine results
in introducing another asymmetric center eg. α-
methyl norepinephrine
 Such substituent (methyl) is essential for action.
 Grps greater than methyl such as ethyl
deminishes α-activity and having beta selectivity
eg. α-ethyl norepinephrine
N
H
H
OH
O
H
O
H C
H3

15. SAR OF ADRENERGIC AGONIST:
❖Substitution over R3:
 If there is only one group then hydroxy group at position
4’ is essential for beta agonistic activity with larger
substituent on nitrogen. Eg. Ritodrine
 Substitution with dihydroxy group over 3’ & 5’ position
result in retaining activity since such compound do not
have good affinity for COMT. Eg. Metaproterenol
N
H
OH
CH3
OH
O
H
N
H
OH
CH3
CH3
CH3
O
H
OH

16. SAR OF ADRENERGIC AGONIST:
Continue……….
 However substitution at 2’& 5’ position with dimethoxy
group result in selective alpha agonistic activity in addition
to beta blocking activity at higherconcentration. Eg.
Methoxamine
 When aromatic ring is unsubstituted the compound are
found to exhibit both selectivity and nonselectivity.
N
H
H
OH
CH3
O
O
C
H3
C
H3

17. SYNTHESIS OF NEWER ADRENERGIC AGONISTS:
Bitolterol
➢ It is an beta-2 adrenergic agonist causes relaxation of
smooth muscle surrounding the air flow tubes.
➢ SYNTHESIS:
NH
O
O
H
CH3
CH3
C
H3
O
H
NH
O
O
C
H3
CH3
CH3
O
O
C
H3
O
C
H3
N
OH
O
O
O
C
H3
O
C
H3
C
H3
CH3
CH3
H
CH4
+
Cl
O
C
H3
2-(tert-butylamino)-1-(3,4-
dihydroxyphenyl)ethanone
4-methylbenzoyl chloride
Reduction
Bitolterol

18. BRIMONIDINE:
 Brimonidine is an α2-adrenergic agonist, through the activation
of Gi GPCR, it inhibit the production of AC. This reduces cAMP
and hence aqueous humour production by the ciliary body.
 It is used in treatment of open angle glaucoma or ocular
hypertension.
 Synthesis:
N
N
NH2
Br
N
H
N
O
CH3
O
N
N
NH
Br
N
N
CH3
O
N
N
NH
Br
N
NH
+
6-amino-5-
bromoquinoxaline
1-acetylimidazolidin-2-one
Brimonidine
POCl3
Condensation
Hydrolysis