Group III metabotropic glutamate receptors (mGluRs) are thought to modulate neurotoxicity of excitatory amino acids, via mechanisms of presynaptic inhibition, such as regulation of neurotransmitter release. Here, we describe (R,S)-4-phosphonophenylglycine (PPG) as a novel, potent, and selective agonist for group III mGluRs. In recombinant cell lines expressing the human receptors hmGluR4a, hmGluR6, hmGluR7b, or hmGluR8a, EC 50 values for (R,S)-PPG of 5.2 ± 0.7 μM, 4.7 ± 0.9 μM, 185 ± 42 μM, and 0.2 ± 0.1 μM, respectively, were measured. The compound showed EC 50 and IC 50 values of ≥200 μM at group I and II hmGluRs and was inactive at cloned human N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4- propionate, and kainate receptors (>300 μM). On the other hand, it showed micromolar affinity for a Ca 2+/CI -dependent L-glutamate binding site in rat brain, similar to other phosphono-substituted amino acids like L-2- amino-4-phosphonobutyrate. In cultured cortical neurons, (R,S)-PPG provided protection against a toxic pulse of N-methyl-D-aspartate (EC 50 = 12 μM), which was reversed by the group III mGluR antagonist (R,S)-α-methylserine- O-phosphate but not by the group II antagonist (2S)-α-ethylglutamate. Moreover, (R,S)-PPG protected against N-methyI-D-aspartate- and quinolinic acid-induced striatal lesions in rats and was anticonvulsive in the maximal electroshock model in mice. In contrast to the group III mGluR agonists L-2- amino-4-phosphonobutyrate and b-serine-O-phosphate, (R,S)-PPG showed no proconvulsive effects (2200 nmol i.c.v.). These data provide novel in vivo evidence for group III mGluRs as attractive targets for neuroprotective and anticonvulsive therapy. Also, (R,S)-PPG represents an attractive tool to analyze the roles of group III mGluRs in nervous system physiology and pathology.
|Number of pages||10|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Jun 1999|
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