Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers

• Published in: Journal of medicinal chemistry Vol. 47; no. 9; pp. 2176 - 2179
• Main Authors: Sternfeld, Francine, Carling, Robert W, Jelley, Richard A, Ladduwahetty, Tamara, Merchant, Kevin J, Moore, Kevin W, Reeve, Austin J, Street, Leslie J, O'Connor, Desmond, Sohal, Bindi, Atack, John R, Cook, Susan, Seabrook, Guy, Wafford, Keith, Tattersall, F David, Collinson, Neil, Dawson, Gerard R, Castro, José L, MacLeod, Angus M
• Format: Journal Article
• Language: English
• Published: United States 22-04-2004
• Subjects: Animals; Binding, Competitive; Biological Availability; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Convulsants - chemical synthesis; Convulsants - chemistry; Convulsants - pharmacology; Dogs; GABA-A Receptor Agonists; Humans; Macaca mulatta; Mice; Nootropic Agents - chemical synthesis; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Oocytes - metabolism; Patch-Clamp Techniques; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Radioligand Assay; Rats; Receptors, GABA-A - physiology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Xenopus laevis
• ISSN: 0022-2623

Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.