Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent

被引：36

作者：

Anzini, Maurizio ^{[1
,2
]}

Braile, Carlo ^{[1
,2
]}

Valenti, Salvatore ^{[1
,2
]}

Cappelli, Andrea ^{[1
,2
]}

Vomero, Salvatore ^{[1
,2
]}

Marinelli, Luciana ^{[3
]}

Limongelli, Vittorio ^{[3
]}

Novellino, Ettore ^{[3
]}

Betti, Laura ^{[4
]}

Giannaccini, Gino ^{[4
]}

Lucacchini, Antonio ^{[4
]}

Ghelardini, Carla ^{[5
]}

Norcini, Monica ^{[5
]}

Makovec, Francesco ^{[7
]}

Giorgi, Gianluca ^{[6
]}

Fryer, R. Ian ^{[8
]}

机构：

[1] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy

[2] Univ Siena, European Res Ctr Drug Discovery & Dev, I-53100 Siena, Italy

[3] Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy

[4] Univ Pisa, Dipartimento Psichiatria Neurobiol Farmacol & Bio, I-56126 Pisa, Italy

[5] Univ Florence, Dipartimento Farmacol Preclin & Clin M Aiazzi Man, I-50139 Florence, Italy

[6] Rottapharm SpA, I-20052 Monza, Italy

[7] Univ Siena, Dipartimento Chim, I-53100 Siena, Italy

[8] Rutgers State Univ, Dept Chem, Newark, NJ 07102 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 15期

关键词：

D O I：

10.1021/jm8002944

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4730 / 4743

页数：14

共 83 条

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