Structure–Activity Relationship-H1 Receptor

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.