Paper Citing NAMD - Abstract
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; Fryer, R. Ian
Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbox ylate as novel, highly potent, and safe antianxiety agent
JOURNAL OF MEDICINAL CHEMISTRY, 51:4730-4743, AUG 14 2008
Ethyl 8-fluoro-6-(4-nitrophenyl)- and ethyl 8-fluoro-6-(3-nitrophenyl)-4H-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.
