Chemical biology & drug design, 2019-04, Vol.93 (4), p.511-521
2019
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- Autor(en) / Beteiligte
- Titel
- Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities
- Ist Teil von
- Chemical biology & drug design, 2019-04, Vol.93 (4), p.511-521
- Ort / Verlag
- England
- Erscheinungsjahr
- 2019
- Quelle
- Wiley Online Library Journals【Remote access available】
- Beschreibungen/Notizen
- A series of 2‐pyrimidinyl‐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‐HT1A, 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‐HT1A. 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‐HT1A 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 Papp 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. From the series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione, compound 4b behaved as antagonist of 5‐HT1A with antidepressant‐ and anxiolytic‐like activity. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1747-0277eISSN: 1747-0285DOI: 10.1111/cbdd.13442Titel-ID: cdi_proquest_miscellaneous_2132732156
- Format
- –
- Schlagworte
- Animals, Anti-Anxiety Agents - chemistry, Anti-Anxiety Agents - metabolism, Anti-Anxiety Agents - pharmacology, antidepressants, Antidepressive Agents - chemistry, Antidepressive Agents - metabolism, Antidepressive Agents - pharmacology, anxiolytics, Binding Sites, buspirone, Imidazoles - chemistry, Maze Learning - drug effects, Mice, Microsomes, Liver - drug effects, Microsomes, Liver - metabolism, Molecular Dynamics Simulation, PDE inhibitors, Permeability - drug effects, Phosphoric Diester Hydrolases - chemistry, Phosphoric Diester Hydrolases - metabolism, Piperazine - chemistry, Protein Binding, Protein Structure, Tertiary, Purines - chemistry, Purines - metabolism, Purines - pharmacology, Pyrimidines - chemistry, Receptor, Serotonin, 5-HT1A - chemistry, Receptor, Serotonin, 5-HT1A - metabolism, serotonin receptors ligands, Structure-Activity Relationship