Synthesis, in Vivo Evaluation, and Molecular Modeling Studies of New Pyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide Derivatives. Identification of a Bifunctional Hydrogen Bond Area Related to the Inverse Agonism

被引：21

作者：

Guerrini, Gabriella ^{[1
]}

Ciciani, Giovanna ^{[1
]}

Cambi, Giovanni ^{[1
]}

Bruni, Fabrizio ^{[1
]}

Selleri, Silvia ^{[1
]}

Guarino, Chiara ^{[1
]}

Melani, Fabrizio ^{[2
]}

Montali, Marina ^{[3
]}

Martini, Claudia ^{[3
]}

Ghelardini, Carla ^{[4
]}

Norcini, Monica ^{[4
]}

Costanzo, Annarella ^{[1
]}

机构：

[1] Univ Florence, Lab Progettaz Sintesi & Studio Etercocili Biologi, Dipartimento Sci Farmaceut, I-50019 Sesto Fiorentino, Italy

[2] Univ Florence, Lab Mol Modeling Cheminformat & QSAR, Dipartimento Sci Farmaceut, I-50019 Sesto Fiorentino, Italy

[3] Univ Pisa, Dipartimento Psichiat Neurobiol Farmacol & Biotec, I-56126 Pisa, Italy

[4] Univ Florence, Dipartimento Farmacol Preclin & Clin Aiazzi Manci, I-50139 Florence, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 15期

关键词：

BENZODIAZEPINE-RECEPTOR LIGANDS; GABA(A) RECEPTORS; PHARMACOLOGICAL EVALUATION; SUBTYPE; SCHIZOPHRENIA; DYSFUNCTION; MODULATORS; COGNITION; EFFICACY; THERAPY;

D O I：

10.1021/jm801599a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of pyrazolo[5,1-c-][1,2,4]benzotriazine 5-oxide 8-alkyloxy-/aryloxy-/arylalkyloxy and 8-aryl-/arylalkylderivatives variously substituted at the 3-position were synthesized and binding studies at the benzodiazepine site on GABA(A) receptor were carried out. The pharmacological profile was identified for compounds 10, 11, 16(+), 16(-), and 17 by considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motility and explorative activity, potential anxiolytic-like effects, mouse learning and memory modulation., and finally, ethanol-potentiating action. Compound 17 stands out as the compound that improves mouse memory processes selectively, safely, and in a statistically significant manner. From a ligand-based pharmacophoric model, we identified a hydrogen bond interaction area HBp-3 near the lipophilic area. This new pharmacophoric model allowed us to identify four structural compound typologics and thus to rationalize the affinity data of all compounds.

引用

页码：4668 / 4682

页数：15

共 37 条

[11] Benzodiazepine receptor ligands.: 8:: Synthesis and pharmacological evaluation of new pyrazolo[5,1-c] [1,2,4]benzotriazine 5-oxide 3-and 8-disubstituted:: High affinity ligands endowed with inverse-agonist pharmacological efficacy [J].