title: Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent.
abstract: 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.
authors.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
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Carlo
authors.initials: C
authors.lastname: Braile
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Monica
authors.initials: M
authors.lastname: Norcini
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: R
authors.initials: R
authors.lastname: Ian Fryer
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D007093:Imidazoles; C531195:ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylate; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole