CIS-2,4-METHANOGLUTAMATE IS A POTENT AND SELECTIVE N-METHYL-D-ASPARTATE RECEPTOR AGONIST

Cis- and trans-2,4-methanoglutamate were compared with L-glutamate as acidic amino acid ligands. Cis-2,4-methanoglutamate had a Ki of 0.052 μM against N-methyl-D-aspartate (NMDA)-specific L-[3H]glutamate binding compared with 0.050 μM for L-glutamate. Cis-2,4-methanoglutamate exhibited no significant affinity against [3H]kainate or [3H]α-amino-3-hydroxy-5-methyl-4-isoxazole propionate ([3H]AMPA) binding. Trans-2,4-methanoglutamate had no significant affinity for any of these sites. Cis-2,4-methanoglutamate increased [3H]N-1[2-thienyl]cyclohexyl-3, 4-piperidine ([3H]TCP) binding with EC50 of 0.35 ± 0.14 μM. It produced an inward current in rat brain mRNA-injected Xenopus oocytes which was blocked by the NMDA antagonist, D-2-amino-7-phosphonoheptanoate (D-AP7). Cis-2,4-methanoglutamate (EC50 = 15.9 μM) was 100-fold more potent than L-glutamate (EC50 = 1,584 μM) in reducing the excitatory postsynaptic potential in CA1 of hippocampal slices. Cis-2,4-methanoglutamate is the most potent, selective NMDA agonist known. © 1990.