New Insight into the Central Benzodiazepine Receptor鈥揕igand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4

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• 作者：Maurizio Anzini ; Salvatore Valenti ; Carlo Braile ; Andrea Cappelli ; Salvatore Vomero ; Stefano Alcaro ; Francesco Ortuso ; Luciana Marinelli ; Vittorio Limongelli ; Ettore Novellino ; Laura Betti ; Gino Giannaccini ; Antonio Lucacchini ; Simona Daniele ; Claudia Martini ; Carla Ghelardini ; Lorenzo Di Cesare Mannelli ; Gianluca Giorgi ; Maria Paola Mascia ; Giovanni Biggio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5694-5711
• 全文大小：1347K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K_i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of ³⁶Cl^{鈥?/sup> in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant 伪₁尾₂纬₂L, 伪₂尾₁纬₂L, and 伪₅尾₂纬₂L human GABA_A receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer鈥檚 GABA_A homology model.}