A pyridazine series of alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Lewis
Richard T
RT
The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom. richard_t_lewis@btinternet.com
Blackaby
Wesley P
WP
Blackburn
Timothy
T
Jennings
Andrew S R
AS
Pike
Andrew
A
Wilson
Rowan A
RA
Hallett
David J
DJ
Cook
Susan M
SM
Ferris
Pushpinder
P
Marshall
George R
GR
Reynolds
David S
DS
Sheppard
Wayne F A
WF
Smith
Alison J
AJ
Sohal
Bindi
B
Stanley
Joanna
J
Tye
Spencer J
SJ
Wafford
Keith A
KA
Atack
John R
JR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001665:Binding Sites; D018755:GABA Agonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011724:Pyridazines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011724:Pyridazines; D011994:Recombinant Proteins