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

J Med Chem. 2009 Aug 13;52(15):4668-82. doi: 10.1021/jm801599a.

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.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis
  • Anti-Anxiety Agents / pharmacology
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / pharmacology
  • Cattle
  • Drug Inverse Agonism*
  • GABA-A Receptor Agonists*
  • Hydrogen Bonding
  • Male
  • Mice
  • Models, Molecular
  • Motor Activity
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / metabolism
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology

Substances

  • Anti-Anxiety Agents
  • Anticonvulsants
  • GABA-A Receptor Agonists
  • Receptors, GABA-A
  • Triazines