Structure–Activity Relationship-H1 Receptor

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Chapter: Medicinal Chemistry : Antihistamines

The diaryl substitution is essential for significant H1 affinity. It is present both in first generation and second generation antihistamines. The optimal antihistaminic activity depends on the co-planarity of two aryl substitutions.


STRUCTURE ACTIVITY RELATIONSHIP - H1 RECEPTOR ANTAGONISTS


1. Aryl groups

The diaryl substitution is essential for significant H1 affinity. It is present both in first generation and second generation antihistamines. The optimal antihistaminic activity depends on the co-planarity of two aryl substitutions.

Active aryl substitutions are as follows:

Ar is phenyl and hetero aryl group like 2-pyridyl

Ar1-Aryl or aryl methyl group

2. Nature of X

Antihistamines with X = carbon (pheniramine series) represents the stereo selective receptor binding to the receptors due to its chirality.

The active substitutions of X are as follows:

Where X = oxygen (amino alkyl ether analogue)

X = nitrogen (ethylene-diamine derivative)

X = carbon (mono amino propyl analogue)

2. The Alkyl Chain

Most of the antihistamines have ethylene chain, and branching of this chain results in a less active compound.


All antihistamines contain this general chain.

3. Terminal nitrogen atom:

The terminal N-atom should be a 3° amine for maximum activity. The terminal nitrogen may be a part of heterocyclic ring. For example, antazoline and chlorcyclizine, retains high antihistaminic activity. The amino moiety deserves the protonation on interaction with H1 recptor due to the basicity with pka 8.5-10.



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