Condensation of muscimol or thiomuscimol with aminopyridazines yields GABA-A antagonists.
Ten analogs of muscimol and thiomuscimol in which the amino function was delocalized in an amidinic system were prepared by N2 alkylation of 6-aryl-3-aminopyridazines with (chloromethyl)isoxazole or (chloromethyl)isothiazole derivatives. These muscimol and thiomuscimol derivatives show potent binding properties for GABA-A receptors (they displace [3H]GABA and [3H]gabazine) and provoke convulsions after iv injections. They fit well with the model pharmacophore proposed by our group for the GABA-A antagonists and show similar structure-activity profiles to that of the pyridazinyl-GABAs.
Melikian
A
A
Centre de Neurochimie du CNRS, Strasbourg, France.
Schlewer
G
G
Chambon
J P
JP
Wermuth
C G
CG
D000818:Animals; D001667:Binding, Competitive; D003292:Convulsants / Q000138:chemical synthesis; D005260:Female; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009118:Muscimol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship
D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D009118:Muscimol; C020522:thiomuscimol