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

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.