Structurally, substitution(modification) is possible on-
- Aryl group- X = O, C, N
- Ethylene Bridge
- anime group
1. Substitution on Aryl groups
The diary substitution is essential for Activity.
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:
I. Ar is phenyl and hetero aryl group like 2-pyridyl
II. Ar1 is Aryl or aryl methyl group
III. Substitution of Cl, Br, O-CH3 group on aryl ring increase the activity
2. Nature of X
Antihistamines with X = carbon (pheniramine series) represents the stereo selective receptor binding to the receptors due to its chirality.
The X is substituted by three major elements, Nitrogen, Oxygen, Carbon. And If X is substituted by any other element, then the activity will decrease or lost
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)
3. The Alkyl Chain
Most of the antihistamines have ethylene chain which is essential for activity.
Branching of this chain results in a less active compound.
4. 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 which increase the antihistaminic activity by many times.
