Antihypertensive

Agents

Venugopala K.N
Notes
•G-Protein-coupled receptors
•Activate generation of cyclic AMP

β3-Adrenoceptor
•Predominant receptor in fat cells
•Activation results in fat metabolism

β2-Adrenoceptor
•Predominant receptor in bronchial smooth muscle
•Activation results in smooth muscle relaxation

β1-Adrenoceptor
•Predominant receptor in heart muscle
•Activation results in cardiac muscle contraction
•Antagonists of this receptor are potential cardiovascular drugs
2. Natural messengers

Noradrenaline - neurotransmitter Adrenaline - hormone

Notes
•Activate all adrenergic receptors
•No selectivity
3. Lead compound

Isopropyl group

Isoprenaline

•Isoprenaline is a β-agonist rather than non

selective β agonist
•Shows selectivity for β-adrenoceptors
•N-Isopropyl group is responsible for selectivity
4. Converting an agonist to a partial antagonist

Isoprenaline Pronethalol
Dichloroisoprenaline
(agonist) (partial
(partial antagonist )
antagonist )

Notes
•Phenol groups are not required for antagonist activity
•Add extra binding groups to convert an agonist to an antagonist
•Hydrophobic groups form extra van der Waals interactions
•Structure binds but produces a different induced fit
•Act as partial agonists
- weakly activate receptors
- block natural messenger
5. Converting a partial antagonist to an antagonist
Spacer
Ether

Pronethalol •Introduce spacer Propranolol

(partial ag) (chain extension) (antagonist)
•Vary substituent position

Notes on propranolol
•Spacer introduced - chain extension strategy
•Substituent is positioned at a different part of the ring
•Ether group acts as a hydrogen bond acceptor (extension strategy)
•10-20 times greater antagonist activity
•Used clinically as a racemate
•S-Enantiomer is the active enantiomer
•Aryloxypropanolamine structure
•Activates β1 and β2 adrenoceptors
6. Synthesis of aryloxypropranolamines

Notes
•Allows variation of aromatic rings and N-substituents
•Racemic products are formed
7. SAR on aryloxypropanolamines
Substitution
Propanolamine group lowers activity
Amine
Ether

N-Alkyl
Alcohol
group

Aryloxy group Naphthalene

Notes
•Ether acts as a hydrogen bond acceptor
•Ether can be replaced with an alternative HBA (O or NH)
•Alcohol is essential as a hydrogen bonding group
•Amine is ionised and forms an ionic bond with the binding site
•Amine must be secondary
•Naphthalene is replacable with heteroaromatic rings
•Branched N-alkyl group fits a hydrophobic pocket
•Extension of N-alkyl group with N-arylethyl group is beneficial
8. Variation of the naphthalene ring

Propranolol Pindolol Timolol

9. Second generation β-blockers
Notes

•Propranolol acts against both β1 and β2-adrenoceptors

•Cannot be used with asthmatic patients

•Antagonism of β2-adrenoceptors constricts airways

•Second generation β-blockers are designed to be β1 -selective

9. Second generation β-blockers
Practolol

Notes
•Selective cardiac β1-antagonist
•More polar
•Less CNS side effects
•First cardioselective β1-blocker used for the treatment of angina and
hypertension
•Withdrawn due to serious side effects in some patients
9. Second generation β-blockers
Practolol - binding interactions
•Amido group must be para for β1-selectivity
•Extra hydrogen bonding interaction takes place
•Not possible with β2-adrenoceptor

O N O N
H2 H2
OH OH
O

H 3C N
H
HN CH 3

H H
X X

para substitution meta substitution

Extra H-bonding interaction
9. Second generation β-blockers
Other agents

Acebutolol Atenolol Metoprolol Betaxolol

10. Third generation β-blockers
Notes
•Includes an N-arylalkyl group
•Additional hydrogen bonding interactions are possible
•Extension strategy

Primidolol
Epanolol

Xamoterol
Extra H-bonding interactions