4-Alkyl- And 4-cinnamylglutamic Acid Analogues Are Potent GluR5 Kainate Receptor Agonists

J Med Chem. 2000 May 18;43(10):1958-68. doi: 10.1021/jm9911682.

Abstract

Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.

MeSH terms

  • Acetylene / chemistry
  • Cell Line
  • Cells, Cultured
  • Electrophysiology
  • Ganglia, Spinal / physiology
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry*
  • Glutamates / metabolism
  • Glutamates / pharmacology
  • Humans
  • Molecular Structure
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Receptors, AMPA / metabolism
  • Receptors, Kainic Acid / agonists*
  • Receptors, Kainic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Structure-Activity Relationship

Substances

  • 2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid
  • Gluk1 kainate receptor
  • Glutamates
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Acetylene