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Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1 ‐f ]purine‐2,4(3 H ,8 H )‐dione with antidepressant‐ and anxiolytic‐like activities
Author(s) -
Zagórska Agnieszka,
Partyka Anna,
Bucki Adam,
Kołaczkowski Marcin,
JastrzębskaWięsek Magdalena,
Czopek Anna,
Siwek Agata,
GłuchLutwin Monika,
Bednarski Marek,
Bajda Marek,
Jończyk Jakub,
Piska Kamil,
Koczurkiewicz Paulina,
Wesołowska Anna,
Pawłowski Maciej
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13442
Subject(s) - chemistry , buspirone , metabolic stability , anxiolytic , stereochemistry , in silico , pharmacology , in vitro , receptor , biochemistry , serotonin , biology , gene
A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1 ‐f ]purine‐2,4(3 H ,8 H )‐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‐ HT 7 , and phosphodiesterases PDE 4 and PDE 10. 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 system. Experimentally obtained value of apparent permeability coefficient P app for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities 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.