Γ-aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and hydroxamates

J Med Chem. 2013 Jul 11;56(13):5626-30. doi: 10.1021/jm4006548. Epub 2013 Jun 27.

Abstract

Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Binding, Competitive
  • Chemistry, Pharmaceutical / methods*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology
  • Female
  • GABA Antagonists / chemistry*
  • GABA Antagonists / pharmacology*
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Membrane Potentials / drug effects
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Receptors, GABA / chemistry
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism*
  • Xenopus laevis

Substances

  • Amides
  • Cyclopentanes
  • GABA Antagonists
  • GABA-C receptor
  • Hydroxamic Acids
  • Receptors, GABA