6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists.
Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.
Chambers
Mark S
MS
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. mark_chambers@merck.com
Atack
John R
JR
Bromidge
Frances A
FA
Broughton
Howard B
HB
Cook
Susan
S
Dawson
Gerard R
GR
Hobbs
Sarah C
SC
Maubach
Karen A
KA
Reeve
Austin J
AJ
Seabrook
Guy R
GR
Wafford
Keith
K
MacLeod
Angus M
AM
D000818:Animals; D002478:Cells, Cultured; D003071:Cognition; D058785:GABA-A Receptor Agonists; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014982:Xenopus laevis
C452421:6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one; D058785:GABA-A Receptor Agonists; D007659:Ketones; D013844:Thiazoles; D013876:Thiophenes