H1-Antagonists

Tutorial Class
MOA of H1-antihistamines
• H1-antihistamines act as inverse agonists that combine with and
stabilize the inactive form of the H1-receptor, shifting the
equilibrium toward the inactive state

• In this way, these drugs effectively antagonize the actions of

histamine at H1-receptors
MOA
Classification
Chemical class Drugs
Ethylenediamines Tripelenamine
Ethanolamines Clemastine, Dimenhydrinate,
Diphenhydramine, Doxylamine
Cyclizine, Chlorcyclizine,
Piperazines
Meclizine, Buclizine
Alkylamines Pheniramine, Chlorpheniramine,
Triprolidine
Phenothiazines Promethazine, Trimeperazine
Dibenzocycloheptenes and Cyproheptadine, Azatadine
dibenzocycloheptanes
SAR of H1 receptor antagonists
• The Structural requirements are:
Tertiary Amino
Group
Aromatic
Groups

Alkyl
Connecting Chain
Moiety
(N, C, O)
1. Aromatic groups
• Diaryl substitution is essential for significant H1-receptor affinity
• The active aryl substitution are: Phenyl, substituted phenyl, 2-
pyridyl
• The substitution in one of the aryl rings – mainly in phenyl ring
results in increased activity.
• Disubstitution - ↓ activity
• The two aryl rings may be linked, e.g. promethazine,
cyproheptadine
2. Nature of Connecting Moiety ‘X’
X = CHO (aminoalkyl ethers)
X = N (Ethylene diamines), CHN (Piperazines)
X = CH (propylamines)
• Carbon atom results in Asymmetry (Chiraity) → Stereoselective
binding
• S isomer shows higher H1-receptor binding affinity
3. Alkyl chain
• The distance between the ‘X’ and terminal nitrogen – 5-6 Å
• May be 2 to 3 carbon atoms long
• Branching of carbon chain ↓ activity (except ????)
• Unsaturation in carbon chain retains activity (e.g. ?????)
4. Terminal Nitrogen atom
• Should be a tertiary amine for maximum activity
• May be a part of heterocyclic ring (Examples????)
• Amino moiety is essential for salt formation (hydrochloride salts,
tartarate, succinate, etc.)
• Large substitutions are present in 2nd Generation drugs