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

Journal of Medicinal Chemistry
2009.0

Abstract

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 typologies and thus to rationalize the affinity data of all compounds.

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