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

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.