Tricyclic pyridones as functionally selective human GABAA alpha 2/3 receptor-ion channel ligands.
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.
Crawforth
James
J
Department of Medicinal Chemistry, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. james_crawforth@merck.com
Atack
John R
JR
Cook
Susan M
SM
Gibson
Karl R
KR
Nadin
Alan
A
Owens
Andrew P
AP
Pike
Andrew
A
Rowley
Michael
M
Smith
Alison J
AJ
Sohal
Bindi
B
Sternfeld
Francine
F
Wafford
Keith
K
Street
Leslie J
LJ
D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008024:Ligands; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*
C484841:GABRA2 protein, human; D008024:Ligands; D021122:Protein Subunits; D011728:Pyridones; D011963:Receptors, GABA-A