Synthesis and bioactivity of a new class of rigid glutamate analogues. Modulators of the N-methyl-D-aspartate receptor

J Med Chem. 1990 Jun;33(6):1561-71. doi: 10.1021/jm00168a007.

Abstract

A variety of derivatives of azetidine-2,4-dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (10f) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-aspartate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of 10f was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine 10f are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine 10f appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50 microM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Azetidinecarboxylic Acid / analogs & derivatives
  • Azetidinecarboxylic Acid / chemical synthesis*
  • Azetidinecarboxylic Acid / pharmacology
  • Azetines / chemical synthesis*
  • Calcium / metabolism*
  • Cells, Cultured
  • Cerebellum / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / drug effects*
  • Structure-Activity Relationship

Substances

  • Azetines
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Azetidinecarboxylic Acid
  • Calcium