High affinity central benzodiazepine receptor ligands: synthesis and biological evaluation of a series of phenyltriazolobenzotriazindione derivatives

J Med Chem. 2005 Apr 21;48(8):2936-43. doi: 10.1021/jm0408722.

Abstract

A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Cattle
  • Cell Line
  • Chlorides / metabolism
  • GABA-A Receptor Agonists*
  • GABA-A Receptor Antagonists*
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Protein Isoforms / agonists
  • Protein Isoforms / antagonists & inhibitors
  • Radioligand Assay
  • Rats
  • Recombinant Proteins / agonists
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • 9-chloro-2-phenyl-(1,2,3)triazolo(1,2-a)(1,2,4)benzotriazin-1,5(6H)-dione
  • Chlorides
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Protein Isoforms
  • Recombinant Proteins
  • Triazines
  • Triazoles