gamma-Aminobutyrate-A receptor modulation by 3-aryl-1-(arylsulfonyl)- 1,4,5,6-tetrahydropyridazines.
A series of 3-aryl-1-(arylsulfonyl)-1,4,5,6-tetrahydropyridazine allosteric modulators of the GABAA receptor was synthesized, and biological activity was examined in vitro and in vivo. Beginning with 1a, stepwise modification of the substituents and conservation of the scaffold yielded a chemical series in which the modulatory activity was enhanced by the presence of GABA. The SAR suggests, but does not establish, that the compounds bind to the steroid binding site on the GABAA receptor. The GABA shift for each compound indicates that all compounds in this series are either agonists or partial agonists.
The R. W. Johnson Pharmaceutical Research Institute, Route 202, P.O. Box 300, Raritan, New Jersey 08876, USA.
P J
PJ
Rybczynski
D W
DW
Combs
K
K
Jacobs
R P
RP
Shank
B
B
Dubinsky
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001933:Brain Stem / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011724:Pyridazines; D010433:Pentylenetetrazole