The Synthesis and Evaluation of Fluoro-, Trifluoromethyl-, and Iodomuscimols as GABA Agonists

Chemistry. 2017 Aug 10;23(45):10848-10852. doi: 10.1002/chem.201701443. Epub 2017 Jul 24.

Abstract

Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α1 β2 γ2 ) and extrasynaptic (α4 β2 γ) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α4 β2 γ) receptor.

Keywords: gaba agonists; gaba receptors fluorination; iodination; muscimol; trifluoromethyl.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Fluorine / chemistry*
  • GABA Agonists / chemical synthesis
  • GABA Agonists / chemistry*
  • GABA Agonists / metabolism
  • Molecular Conformation
  • Muscimol / chemical synthesis
  • Muscimol / chemistry*
  • Muscimol / metabolism
  • Oocytes / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Xenopus laevis / growth & development
  • Xenopus laevis / metabolism

Substances

  • GABA Agonists
  • Receptors, GABA-A
  • Muscimol
  • Fluorine