Ethyl 8-fluoro-6-(4-nitrophenyl)- and ethyl 8-fluoro-6-(3-nitrophenyl)-4 H-imidazo[1,5-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.
|Autori:||Anzini M.; Braile C.; Valenti S.; Cappelli A.; Vomero S.; Marinelli L.; Limongelli V.; Novellino E.; Betti L.; Giannaccini G.; Lucacchini A.; Ghelardini C.; Norcini M.; Makovec F.; Giorgi G.; Fryer RI.|
|Titolo:||Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo1,5-a1,4benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent|
|Anno del prodotto:||2008|
|Digital Object Identifier (DOI):||10.1021/jm8002944|
|Appare nelle tipologie:||1.1 Articolo in rivista|