title: High affinity central benzodiazepine receptor ligands: synthesis and biological evaluation of a series of phenyltriazolobenzotriazindione derivatives.
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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. primofiore@farm.unipi.it
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: François
authors.initials: F
authors.lastname: Besnard
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Marina
authors.initials: M
authors.lastname: Montali
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D051381:Rats; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C500623:9-chloro-2-phenyl-(1,2,3)triazolo(1,2-a)(1,2,4)benzotriazin-1,5(6H)-dione; D002712:Chlorides; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014227:Triazines; D014230:Triazoles