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Condensation of muscimol or thiomuscimol with aminopyridazines yields GABA-A antagonists.

Abstract
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.
AuthorsA Melikian, G Schlewer, J P Chambon, C G Wermuth
JournalJournal of medicinal chemistry (J Med Chem) Vol. 35 Issue 22 Pg. 4092-7 (Oct 30 1992) ISSN: 0022-2623 [Print] United States
PMID1331456 (Publication Type: Journal Article)
Chemical References
  • Convulsants
  • GABA-A Receptor Antagonists
  • Pyridazines
  • Receptors, GABA-A
  • Muscimol
  • thiomuscimol
Topics
  • Animals
  • Binding, Competitive
  • Convulsants (chemical synthesis)
  • Female
  • GABA-A Receptor Antagonists
  • In Vitro Techniques
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Muscimol (analogs & derivatives, chemical synthesis, metabolism, pharmacology)
  • Pyridazines (chemical synthesis, metabolism, pharmacology)
  • Radioligand Assay
  • Rats
  • Receptors, GABA-A (metabolism)
  • Structure-Activity Relationship

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