Selective mGluR1 Antagonist EMQMCM Inhibits the Kainate-Induced Excitotoxicity in Primary Neuronal Cultures and in the Rat Hippocampus

Abundant evidence suggests that indirect inhibitory modulation of glutamatergic transmission, via metabotropic glutamatergic receptors (mGluR), may induce neuroprotection. The present study was designed to determine whether the selective antagonist of mGluR1 (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), showed neuroprotection against the kainate (KA)-induced excitotoxicity in vitro and in vivo. In in vitro studies on mouse primary cortical and hippocampal neuronal cultures, incubation with KA (150 μM) induced strong degeneration [measured as lactate dehydrogenase (LDH) efflux] and apoptosis (measured as caspase-3 activity). EMQMCM (0.1–100 μM) added 30 min to 6 h after KA, significantly attenuated the KA-induced LDH release and prevented the increase in caspase-3 activity in the cultures. Those effects were dose- and time-dependent. In in vivo studies KA (2.5 nmol/1 μl) was unilaterally injected into the rat dorsal CA1 hippocampal region. Degeneration was calculated by counting surviving neurons in the CA pyramidal layer using stereological methods. It was found that EMQMCM (5–10 nmol/1 μl) injected into the dorsal hippocampus 30 min, 1 h, or 3 h (the higher dose only) after KA significantly prevented the KA-induced neuronal degeneration. In vivo microdialysis studies in rat hippocampus showed that EMQMCM (100 μM) significantly increased γ-aminobutyric acid (GABA) and decreased glutamate release. When perfused simultaneously with KA, EMQMCM substantially increased GABA release and prevented the KA-induced glutamate release. The obtained results indicate that the mGluR1 antagonist, EMQMCM, may exert neuroprotection against excitotoxicity after delayed treatment (30 min to 6 h). The role of enhanced GABAergic transmission in the neuroprotection is postulated

Synthesis and inhibitory activities at mGluRs of 3-alkylated and N-alkylated cyclopentyl-glutamate analogues

The conformationally restricted glutamate analogues, 3-alkyl-1-amino-2- cyclopentene-1,3-dicarboxylates and N-alkylated analogues have been prepared in a regioselective and diastereoselective manner. From the biological studies of the 3-alkylated analogues, compound 13b was found to be the most potent antagonist (IC50 7.7 μM) at mGluR2. Amongst the N-alkylated analogues, compound 20 was found to be a partial agonist (EC50 9.5 μM) and as well as an antagonist (IC50 47 μM) at mGluR2. © 2013 Elsevier Ltd. All rights reserved

Synthesis and antagonist activities of 4-aryl-substituted conformationally restricted cyclopentenyl and cyclopentanyl-glutamate analogues

The conformationally restricted glutamate analogues, 4-aryl-1-amino-2- cyclopentene-1,3-dicarboxylates and their cyclopentane analogues have been prepared in a diastereoselective manner. Biological studies of 12a and 12b indicates that both compounds are modest antagonists at mGluR2. © 2004 Elsevier Ltd. All rights reserved