Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent |
| |
Authors: | Anzini Maurizio Braile Carlo Valenti Salvatore Cappelli Andrea Vomero Salvatore Marinelli Luciana Limongelli Vittorio Novellino Ettore Betti Laura Giannaccini Gino Lucacchini Antonio Ghelardini Carla Norcini Monica Makovec Francesco Giorgi Gianluca Ian Fryer R |
| |
Affiliation: | Dipartimento Farmaco Chimico Tecnologico, European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A Moro, 53100 Siena, Italy. anzini@unisi.it |
| |
Abstract: | Ethyl 8-fluoro-6-(4-nitrophenyl)- and ethyl 8-fluoro-6-(3-nitrophenyl)-4 H-imidazo1,5-a]1,4]benzodiazepine 3-carboxylate 6 and 7 were synthesized as central benzodiazepine receptor (CBR) ligands and tested for their ability to displace (3)H]flumazenil from bovine and human cortical brain membranes. Both compounds showed high affinity for bovine and human CBR. In particular, compound 7 emerged as the most interesting compound, having a partial agonist profile in vitro while possessing useful activity in various animal models of anxiety. In accordance with its partial agonist profile, compound 7 was devoid of typical benzodiazepine side effects. The homology model of the GABA A receptor developed by Cromer et al. was used to assess the binding modes of ligands 6 and 7. From our docking results, the partial agonist activity elicited by compound 7 is likely to be due to the 3'-nitro substituent, which is in the appropriate position to interact with Thr193 of the gamma 2-subunit by means of a hydrogen bond. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|