Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers.
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.
Sternfeld
Francine
F
The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. francine_sternfeld@merck.com
Carling
Robert W
RW
Jelley
Richard A
RA
Ladduwahetty
Tamara
T
Merchant
Kevin J
KJ
Moore
Kevin W
KW
Reeve
Austin J
AJ
Street
Leslie J
LJ
O'Connor
Desmond
D
Sohal
Bindi
B
Atack
John R
JR
Cook
Susan
S
Seabrook
Guy
G
Wafford
Keith
K
Tattersall
F David
FD
Collinson
Neil
N
Dawson
Gerard R
GR
Castro
José L
JL
MacLeod
Angus M
AM
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
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D058785:GABA-A Receptor Agonists; D018697:Nootropic Agents; D010793:Phthalazines; D011963:Receptors, GABA-A; D014230:Triazoles