Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones

Bioorg Med Chem Lett. 2018 Sep 1;28(16):2697-2700. doi: 10.1016/j.bmcl.2018.04.003. Epub 2018 Apr 7.

Abstract

β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.

Keywords: Agonist; Fluorine; GABA receptor; GABA-B; Gamma-aminobutyric acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • GABA-B Receptor Agonists / chemical synthesis
  • GABA-B Receptor Agonists / chemistry
  • GABA-B Receptor Agonists / pharmacology*
  • HEK293 Cells
  • Humans
  • Ketones / chemical synthesis
  • Ketones / chemistry
  • Ketones / pharmacology*
  • Molecular Docking Simulation
  • Propylamines / chemical synthesis
  • Propylamines / chemistry
  • Propylamines / pharmacology*
  • Receptors, GABA-B / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • GABA-B Receptor Agonists
  • Ketones
  • Propylamines
  • Receptors, GABA-B