A series of 2-phenyl[1,2,3]triazolo[1,2-α][1,2,4]benzotriazin-1,5(6H) -diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these B 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 α1β2γ2, α2β 2γ2, and α5β3γ2 GABA A/Bz receptor subtypes, showed enhanced affinities for the α1β2γ2 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 α1 and α2 receptor subtypes, and an antagonist efficacy at B α5-containing receptors
High Affinity Central Benzodiazepine Receptor Ligands: Synthesis and Biological Evaluation of a Series of Phenyltriazolobenzotriazindione Derivatives (PTBTs)
DA SETTIMO PASSETTI, FEDERICO;TALIANI, SABRINA;SALERNO, SILVIA;COSTA, BARBARA;MARTINI, CLAUDIA
2005-01-01
Abstract
A series of 2-phenyl[1,2,3]triazolo[1,2-α][1,2,4]benzotriazin-1,5(6H) -diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these B 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 α1β2γ2, α2β 2γ2, and α5β3γ2 GABA A/Bz receptor subtypes, showed enhanced affinities for the α1β2γ2 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 α1 and α2 receptor subtypes, and an antagonist efficacy at B α5-containing receptorsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
