Synthesis and bioactivity of a new class of rigid glutamate analogs. Modulators of the N-methyl-D-aspartate receptor
- 1 June 1990
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 33 (6) , 1561-1571
- https://doi.org/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 .mu.M.Keywords
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