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

H1 receptor antagonists are classified based on their chemical structure into the following groups: Ethylenediamines (e.g., Mepyramine), Ethanolamines (e.g., Diphenhydramine), Alkylamines (e.g., Chlorpheniramine, Triprolidine), Piperazines (e.g., Cyclizine), and Tricyclic compounds (e.g., Promethazine).

The synthesis of Triprolidine hydrochloride involves a Mannich reaction followed by a Grignard reaction and dehydration:

1. 2-Pyridyl-2-methyl ketone is reacted with formaldehyde and pyrrolidine (Mannich reaction) to form the corresponding Mannich base.
2. This base undergoes a Grignard reaction with 4-methylphenylmagnesium bromide to yield a tertiary alcohol.
3. The alcohol is subsequently dehydrated using an acid catalyst (e.g., HCl) to produce Triprolidine, which is then converted to its hydrochloride salt.

H2 receptor antagonists include agents like Cimetidine, Ranitidine, and Famotidine. These molecules typically feature an imidazole ring (Cimetidine) or a furan/thiazole ring (Ranitidine/Famotidine) linked to a polar, non-basic side chain (e.g., guanidine or diamino-nitroethene).

Structure-Activity Relationship (SAR):

• The aromatic ring is essential for binding; replacing the imidazole ring with other heterocycles often improves potency and reduces side effects.
• The side chain must be flexible and contain a polar, non-basic group to interact with the receptor.
• The optimal distance between the ring and the polar group is approximately four methylene units.

Mode of Action: H2 antagonists act as competitive, reversible inhibitors of histamine at the H2 receptors located on the gastric parietal cells. By blocking these receptors, they prevent histamine-stimulated cyclic AMP production, thereby inhibiting basal and meal-stimulated gastric acid secretion.