title: 3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: tricyclic heteroaromatic derivatives as a new class of benzodiazepine receptor ligands.
abstract: A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Primofiore
authors.forename: F
authors.initials: F
authors.lastname: Da Settimo
authors.forename: S
authors.initials: S
authors.lastname: Taliani
authors.forename: A M
authors.initials: AM
authors.lastname: Marini
authors.forename: C
authors.initials: C
authors.lastname: La Motta
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: M
authors.initials: M
authors.lastname: Gesi
authors.forename: L
authors.initials: L
authors.lastname: Trincavelli
authors.forename: C
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002417:Cattle; D003292:Convulsants / Q000138:chemical synthesis / Q000494:pharmacology; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D001562:Benzimidazoles; D003292:Convulsants; D018757:GABA Modulators; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil; D003975:Diazepam