Synthesis and Biological Evaluation of 3-Heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and Analogues as Subtype-Selective Inverse Agonists for the GABAAα5 Benzodiazepine Binding Site

• Published in: Journal of medicinal chemistry Vol. 47; no. 14; pp. 3642 - 3657
• Main Authors: Street, Leslie J, Sternfeld, Francine, Jelley, Richard A, Reeve, Austin J, Carling, Robert W, Moore, Kevin W, McKernan, Ruth M, Sohal, Bindi, Cook, Susan, Pike, Andrew, Dawson, Gerard R, Bromidge, Frances A, Wafford, Keith A, Seabrook, Guy R, Thompson, Sally A, Marshall, George, Pillai, Goplan V, Castro, José L, Atack, John R, MacLeod, Angus M
• Format: Journal Article
• Language: English
• Published: American Chemical Society 01-07-2004
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0407613

The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABAAα5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of α5- over α1-, α2-, and α3-containing GABAA receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABAAα5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABAAα5 subtype with functional selectivity over the other GABAA receptor subtypes and good oral bioavailability.