Adrenergic agents M. Pharm.

For M. Pharm. (pharmaceutical Chemistry)

1. Presented by:
MohdShafeeque
M. Pharm. 1
st
Sem.
(Pharm. Chemistry)
JamiaHamdard

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

3. INTRODUCTION:
Adrenergicsystemisanevolutionarilyancientdefence
system,whichconsistsoftheorgansandnervesin
whichcatecholamines,noradrenaline(norepinephrine)or
adrenaline(epinephrine)actasneurotransmitteror
neurohormone.
Thesubstancesthatproduceeffectssimilartostimulation
ofsympatheticnervousactivityareknownas
sympathomimeticsoradrenergicstimulants.
Ingeneral,stimulationofsympatheticnervoussystem
causeswhatisknownasa“fight-or-flight”responses.
Theseeffectsincludeanincreasedrateandforceof
heartcontraction,ariseinbloodpressure,ashiftofblood
flowtoskeletalmuscles,dilationofbronchiolesand
pupilsandanincreaseinbloodglucoselevelsthrough
gluconeogenesisandglycogenolysis.

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 Guanethidineand 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 methylatedby 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
Postjuntionalon effector
organs
Blood vessels-
Contraction
Uterus-Contraction
Gland-Secretion
Gut-Relaxation
Heart-Arrythmia(at higher
dose)
Prejunctionalonnerve ending,
also postjunctionalin brain,
pancreatic beta cells and
extrajunctionalin 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 ↑-PGrelease
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
Bloodvessels-
dilation of
arteriole & veins
: fall in BP
Uterus-
relaxation
Urinary tract-
relaxation
Eye-enhance
aqueous
secretion
Adipose tissue-
lipolysis:
increasein free
fatty acid
Selective
agonist
Dobutamine Salbutamol,
Terbutalin
Mirabegron
Selective
antagonist
Metoprolol, Atenololα-methyl
propranolol
Effector
pathway
cAMP↑, Ca++channel ↑

9. Classification of Adrenergic Drugs:
Selectiveα-Adrenergic
Agonists
Selectiveβ-Adrenergic
Agonists
MixedActing
Sympathomimetics
(a)α1–Agonists
❖Phenylethanolamines:
▪Metaraminol
▪Methoxamine
▪Phenylephrine
❖2-Arylimidazoline:
▪Naphazoline
▪Oxymetazoline
▪tetrahydrozoline
(a)β1-Agonists
❖Catecholamines:
▪Dopamine
❖Arylalkylderivative:
▪Dobutamine
❖Phenylpropylamines:
▪Ephedrine
▪Pseudoephedrine
❖Phenylisopropylamin-
es:
▪Amphetamine
▪Methamphetami
-ne
(b) α2-agonists
❖2-Aminoimidazolines:
▪Clonidine
▪Brimonidine
▪Apraclonidine
(b) β2-Agonists
❖Catecholderivatives:
▪Albuterol
▪Solmetrol
❖Acid-ester derivatives:
▪Colterol

10. STRUCTURES:N
H
CH
3
OH
H
OH NH
N
CH
3
CH
3
CH
3
CH
3
CH
3
OH N
H
CH
3
OH
CH
3 NH
N
Cl
Cl N
HOH
H
CH
3
CH
3
CH
3
OH
OH NH
2
CH
3
Epinephrine
Oxymetazoline
Ephedrine
Clonidine
Dopamine
Albuterol AmphetamineNH
2
OH
OH
Phenylephrine
NorepinephrineN
OH
OH
OH
CH
3
H OH
OH
OH
NH
2

11. MECHANISM OF ACTION OF ADRENERGIC AGONISTS:
❖Direct-acting agonists:
✓Produce their effect by directly stimulating the receptor
site.
✓Epinephrine, Norepinephrine, Isoproterenol, Dopamine
❖Indirect-acting agonists:
✓Release endogenous norepinephrinewhich then
stimulates the receptor
✓Amphetamine & Tyramine
❖Mixed-action agonists:
✓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 anaestheticaction 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 grpβto amine is
essential for adrenergic
agonistic activity
R1-substitution on N:
❖With alkyl grpgreater 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 lipophilicgroups : have alpha blocking activity eg.
Labetalol1'
6'
2'
5'
3'
4'
β
αN
H
R
1
OH
R
2R
3

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.
Grpsgreater than methyl such as ethyl
deminishesα-activity and having beta selectivity
eg. α-ethyl norepinephrineN
H
H
OH
OH
OH
CH
3

15. SAR OF ADRENERGIC AGONIST:
❖Substitution over R3:
If there is only one group then hydroxygroup at position
4’ is essential for beta agonistic activity with larger
substituent on nitrogen. Eg. Ritodrine
Substitution with dihydroxygroup over 3’ & 5’ position
result in retaining activity since such compound do not
have good affinity for COMT. Eg. MetaproterenolN
HOH
CH
3
OHOH N
HOH
CH
3
CH
3
CH
3
OH
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 higher concentration. Eg.
Methoxamine
When aromatic ring is unsubstitutedthe compound are
found to exhibit both selectivity and nonselectivity.N
H
H
OH
CH
3
O
O
CH
3
CH
3

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
OH
CH
3
CH
3
CH
3
OH NH
O
O
CH
3
CH
3
CH
3
O
O
CH
3
O
CH
3 N
OH
O
O
O
CH
3
O
CH
3
CH
3
CH
3
CH
3
H
CH
4
+Cl
O
CH
3
2-(tert-butylamino)-1-(3,4-
dihydroxyphenyl)ethanone
4-methylbenzoyl chloride
Reduction
Bitolterol

18. BRIMONIDINE:
Brimonidineis an α2-adrenergic agonist, through the activation
of GiGPCR, it inhibit the production of AC. This reduces cAMP
and hence aqueous humourproduction by the ciliarybody.
It is used in treatment of open angle glaucoma or ocular
hypertension.
Synthesis:N
N
NH
2
Br NH
N
O
CH
3
O N
N
NH
Br
N
N
CH
3
O N
N
NH
Br
N
NH
+
6-amino-5-
bromoquinoxaline
1-acetylimidazolidin-2-one
Brimonidine
POCl3
Condensation
Hydrolysis