Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with an alkyne spacer as GABA uptake inhibitors

Bioorg Med Chem. 2018 Jul 23;26(12):3668-3687. doi: 10.1016/j.bmc.2018.05.049. Epub 2018 Jun 1.

Abstract

In this study, we present the synthesis and structure-activity relationships (SAR) of novel N-substituted nipecotic acid derivatives closely related to (S)-SNAP-5114 (2) in the pursuit of finding new and potent mGAT4 selective inhibitors. By the use of iminium ion chemistry, a series of new N-substituted nipecotic acid derivatives containing a variety of heterocycles, and an alkyne spacer were synthesized. Biological evaluation of the prepared compounds showed, how the inhibitory potency and subtype selectivity for the murine GABA transporters (mGATs) were influenced by the performed modifications.

Keywords: GABA uptake inhibitor; Iminium ion chemistry; Nipecotic acid; mGAT4.

MeSH terms

  • Alkynes / chemistry*
  • Animals
  • GABA Plasma Membrane Transport Proteins / chemistry*
  • GABA Plasma Membrane Transport Proteins / metabolism*
  • GABA Uptake Inhibitors / chemical synthesis*
  • GABA Uptake Inhibitors / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Nipecotic Acids / chemistry*
  • Nipecotic Acids / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Alkynes
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Gabt4 protein, mouse
  • Nipecotic Acids
  • Protein Isoforms
  • gamma-Aminobutyric Acid