Synthesis and Bioactivity of a New Class of Rigid Glutamate Analogues. Modulators of the N-Methyl-D-aspartate Receptor

Alan P. Kozikowski, Werner Tuckmantel, Ian J. Reynolds, Jarda T. Wroblewski

Research output: Contribution to journalArticlepeer-review

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 (lOf) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-a9partate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of lOf 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 lOf are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine lOf 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 50µM.

Original languageEnglish (US)
Pages (from-to)1561-1571
Number of pages11
JournalJournal of medicinal chemistry
Volume33
Issue number6
DOIs
StatePublished - 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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