JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B.Pharmacy IV MEDICINAL CHEMISTRY - II Previous Question Paper (July/August - 2022 - R17)

Antihistamines are pharmacological agents that act as inverse agonists or antagonists at the H1-histamine receptors, effectively blocking the actions of histamine released during allergic reactions. They are primarily used to treat conditions like hay fever, urticaria, and allergic rhinitis.

The Structure-Activity Relationship (SAR) of H1-receptor antagonists generally follows the formula Ar-X-CH2-CH2-N(R)2, where:

1. Aryl Groups (Ar): At least one aromatic ring is essential for binding. Two aromatic rings (phenyl, substituted phenyl, or heterocyclic) increase potency.
2. Linker (X): The X group can be an oxygen atom (ethers), a nitrogen atom (ethylenediamines), or a carbon atom (propylamines).
3. Alkyl Chain: A two-carbon chain between the linker and the amine is optimal for activity.
4. Amine Group: A terminal tertiary amine is required. The two alkyl groups on the nitrogen are typically methyl groups, though they can be part of a heterocyclic ring (e.g., pyrrolidine or piperidine).

Synthesis of Diphenhydramine Hydrochloride: The synthesis involves the reaction of benzhydryl bromide with 2-dimethylaminoethanol in the presence of a base (like sodium carbonate) or via the reaction of benzhydrol with 2-dimethylaminoethyl chloride in the presence of an acid catalyst. The resulting base is then treated with hydrochloric acid to form the stable hydrochloride salt.

Mechanism of Action: Diphenhydramine acts as a competitive H1-receptor antagonist. By binding to the H1-receptors on effector cells (such as smooth muscle in the respiratory tract and blood vessels), it prevents histamine from binding, thereby inhibiting the physiological effects of histamine, such as vasodilation, increased capillary permeability, and smooth muscle contraction. It also possesses significant anticholinergic and sedative properties due to its ability to cross the blood-brain barrier.