Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives

J Med Chem. 2003 Aug 14;46(17):3758-61. doi: 10.1021/jm030821p.

Abstract

New cyclofunctionalized 2,3-benzodiazepines characterized by a triazolone or triazindione ring fused on the "c" edge of the heptatomic nucleus have been prepared. These compounds were evaluated as potential anticonvulsant agents, and some of them proved to be more potent noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) receptor antagonists. In particular, 8,9-dimethoxy-6-(4-bromophenyl)-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-one (5b) was almost 10-fold more active than GYKI-52466 and 3.5-fold more active than Talampanel. Furthermore, 5b potently reduced AMPA-evoked currents in electrophysiological experiments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Benzodiazepines / chemical synthesis*
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology
  • Disease Models, Animal
  • Epilepsy / drug therapy
  • Excitatory Amino Acid Agonists / pharmacology
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Inbred DBA
  • Neurons / drug effects
  • Neurons / physiology
  • Olfactory Pathways / cytology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • 8,9-dimethoxy-6-(4-bromophenyl)-11H-(1,2,4)triazolo(4,5-c)(2,3)benzodiazepin-3(2H)-one
  • Anticonvulsants
  • Excitatory Amino Acid Agonists
  • Receptors, AMPA
  • Triazoles
  • Benzodiazepines
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid