title: Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers.
abstract: 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.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. francine_sternfeld@merck.com
authors.forename: Francine
authors.initials: F
authors.lastname: Sternfeld
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jelley
authors.forename: Tamara
authors.initials: T
authors.lastname: Ladduwahetty
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Merchant
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Moore
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Reeve
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Susan
authors.initials: S
authors.lastname: Cook
authors.forename: Guy
authors.initials: G
authors.lastname: Seabrook
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.forename: F David
authors.initials: FD
authors.lastname: Tattersall
authors.forename: Neil
authors.initials: N
authors.lastname: Collinson
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003292:Convulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D058785:GABA-A Receptor Agonists; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D058785:GABA-A Receptor Agonists; D018697:Nootropic Agents; D010793:Phthalazines; D011963:Receptors, GABA-A; D014230:Triazoles