Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent.
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.
Anzini
Maurizio
M
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
Braile
Carlo
C
Valenti
Salvatore
S
Cappelli
Andrea
A
Vomero
Salvatore
S
Marinelli
Luciana
L
Limongelli
Vittorio
V
Novellino
Ettore
E
Betti
Laura
L
Giannaccini
Gino
G
Lucacchini
Antonio
A
Ghelardini
Carla
C
Norcini
Monica
M
Makovec
Francesco
F
Giorgi
Gianluca
G
Ian Fryer
R
R
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
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