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Selective, Orally Active γ-Aminobutyric AcidA α5 Receptor Inverse Agonists as Cognition Enhancers

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journal contribution
posted on 22.04.2004, 00:00 by Francine Sternfeld, Robert W. Carling, Richard A. Jelley, Tamara Ladduwahetty, Kevin J. Merchant, Kevin W. Moore, Austin J. Reeve, Leslie J. Street, Desmond O'Connor, Bindi Sohal, John R. Atack, Susan Cook, Guy Seabrook, Keith Wafford, F. David Tattersall, Neil Collinson, Gerard R. Dawson, José L. Castro, Angus M. MacLeod
Nonselective inverse agonists at the γ-aminobutyric acidA (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A α5 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.