title: Synthesis and bioactivity of a new class of rigid glutamate analogues. Modulators of the N-methyl-D-aspartate receptor.
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.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pennsylvania 15260.
authors.forename: A P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: W
authors.initials: W
authors.lastname: Tückmantel
authors.forename: I J
authors.initials: IJ
authors.lastname: Reynolds
authors.forename: J T
authors.initials: JT
authors.lastname: Wroblewski
mesh_terms: D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D001385:Azetines / Q000138:chemical synthesis*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001385:Azetines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001383:Azetidinecarboxylic Acid; D002118:Calcium