Trans-2-carboxy-3-pyrrolidineacetic acid (CPAA), a novel agonist at NMDA-type receptors.

Although 2-carboxy-3-pyrrolidineacetic acid (CPAA) analogs are associated with activity as agonists at kainate-type receptors, here we report that CPAA is an agonist at N-methyl-D-aspartic acid-type receptors. CPAA evoked the release of [3H]acetylcholine (ACh) from striatal slices with the same efficacy as NMDA, and an EC50 of 20.0 microM, compared to an EC50 of 45.8 microM for NMDA. CPAA-evoked [3H]ACh release was inhibited by CPP (IC50 = 5.1 microM), tiletamine (IC50 = 0.53 microM), MK-801 (IC50 = 0.12 microM), and MgCl2 (IC50 = 26 microM). CPAA produced a tachyphylaxis when applied continuously for 18 min or more, and a cross-tachyphylaxis to NMDA. Similarly, NMDA generated a cross-tachyphylaxis to CPAA. All of these data suggest that CPAA is an agonist at NMDA-type receptors.