Characteristics of metabolic stability and the cell permeability of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activity

From the series of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione, compound 4b behaved as antagonist of 5‐HT_1A with antidepressant‐and anxiolytic‐like activity. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

Abstract

A series of 2‐pyrimidynyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT_1A, 5‐HT₇ and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione (4b) behaved as strong and selective antagonist of 5‐HT_1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5‐HT_1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes (MLM) system. Experimentally obtained value of apparent permeability coefficient P_app for 4b in parallel artificial permeability assay (PAMPA) indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐and anxiolytic‐like activity of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.

This article is protected by copyright. All rights reserved.

https://ift.tt/2FrxZzz