METHYLATION OF THE NMDA RECEPTOR AGONIST L-TRANS-2,3-PYRROLIDINE-DICARBOXYLATE - ENHANCED EXCITOTOXIC POTENCY AND SELECTIVITY

This study investigated the excitotoxic properties of a novel series o f NMDA analogues in which a methyl group was introduced to the 5-posit ion of the pyrrolidine ring of L-trans-2,3-PDC, a previously identifie d NMDA receptor agonist. While all of these compounds induced NMDA-rec eptor-mediated injury, methylation increased in vivo excitotoxic poten cy 1000-fold. Injections (1 mu l) in rat dorsal hippocampus of cis- an d trans-5-methyl-L-trans-2,3-PDC (0.1 nmol) induced 50-70% neuronal da mage to areas CA1 and CA4, comparable to that induced by 100 nmol of L -trans-2,3-PDC Further, cis- and trans-methylated analogues induced di stinct patterns of hippocampal pathology consistent with differential excitotoxic vulnerability of neurons expressing NMDA receptors. Neuron al damage produced by the 5-methyl-L-trans-2,3-PDCs could be blocked b y coadministration of MK-801 (3 mg/kg ip), but not NBQX (25 nmol). Bio chemical and physiological assays confirmed the action of the analogue s as NMDA agonists, but did not provide an explanation for differences in excitotoxic potency between the methylated and nonmethylated 2,3-P DCs. For example, the activity of the compounds as inhibitors of H-3-g lutamate binding (IC50 values: 0.4, 1.4, and 1.2 mu M for cis-5-methyl -, trans-5-methyl-, and L-trans-2,3-PDC, respectively), agonists at NR 1A/NR2B receptors (EC50 values: 5, 49, and 16 mu M for cis-5-methyl-, trans-5-methyl-, and L-trans-2,3-PDC, respectively), and in vitro exci totoxins in cortical cultures varied only two- to fivefold as a conseq uence of methylation. Potential roles of NMDA receptor subtypes and tr ansport in these effects are discussed. As potent and selective NMDA e xcitotoxins, cis- and trans-5-methyl-L-trans-2,3-PDC will be of value studying excitotoxic mechanisms, NMDA-receptor-mediated pathology, and NMDA receptor heterogeneity. (C) 1997 Academic Press.