Design and synthesis of a new series of 4-alkylated 3-isoxazolol GABA A antagonists

Eur J Med Chem. 2003 Apr;38(4):447-9. doi: 10.1016/s0223-5234(03)00056-4.

Abstract

A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL), in which the 4-position of the 3-isoxazolol ring is substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. While alkyl and benzyl substitution provided affinities and antagonist potencies comparable to those of 4-PIOL, diphenylalkyl and naphthylalkyl substitution resulted in marked increase in both affinity and potency. The 2-naphthylmethyl and the 3,3-diphenylpropyl analogues showed antagonist potencies comparable or markedly higher than that of the standard antagonist SR 95531. Molecular modeling studies exposed a large cavity in the vicinity of the 4-position of 4-PIOL, in which there seems to be additional sites for specific receptor interactions.

Publication types

  • Comparative Study

MeSH terms

  • Alkylation
  • Animals
  • Binding Sites
  • Drug Design*
  • Electrophysiology
  • GABA Antagonists / chemical synthesis*
  • GABA Antagonists / chemistry
  • GABA Antagonists / pharmacology
  • GABA-A Receptor Antagonists*
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Receptors, GABA / drug effects
  • Receptors, GABA / metabolism
  • Receptors, GABA-A / metabolism
  • Structure-Activity Relationship

Substances

  • GABA Antagonists
  • GABA-A Receptor Antagonists
  • Isoxazoles
  • Ligands
  • Pyridazines
  • Receptors, GABA
  • Receptors, GABA-A
  • gabazine