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 bindin...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-10, Vol.35 (22), p.4092-4097
Main Authors: Melikian, Anita, Schlewer, Gilbert, Chambon, Jean Pierre, Wermuth, Camille Georges
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Chemistry
Convulsants - chemical synthesis
Exact sciences and technology
Female
GABA-A Receptor Antagonists
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
In Vitro Techniques
Mice
Models, Molecular
Molecular Conformation
Muscimol - analogs & derivatives
Muscimol - chemical synthesis
Muscimol - metabolism
Muscimol - pharmacology
Organic chemistry
Preparations and properties
Pyridazines - chemical synthesis
Pyridazines - metabolism
Pyridazines - pharmacology
Radioligand Assay
Rats
Receptors, GABA-A - metabolism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00100a015