(R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo

Group III metabotropic glutamate receptors (mGluRs) are thought to modulate neurotoxicity of excitatory amino acids, via mechanisms of presynaptic inh ibition, such as regulation of neurotransmitter release. Here, we describe (R,S)-4-phosphonophenylglycine (PPG) as a novel, potent, and selective agon ist for group III mGluRs. In recombinant cell lines expressing the human re ceptors hmGluR4a, hmGluR6, hmGluR7b, or hmGluR8a, EC50 values for (R,S)-PPG of 5.2 +/- 0.7 mu M, 4.7 +/- 0.9 mu M, 185 +/- 42 mu M, and 0.2 +/- 0.1 mu M, respectively, were measured. The compound showed EC50 and IC50 values o f greater than or equal to 200 mu M at group I and II hmGluRs and was inact ive at cloned human N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyliso xazole-4-propionate, and kainate receptors (>300 mu M). On the other hand, it showed micromolar affinity for a Ca2+/Cl--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 prov ided protection against a toxic pulse of N-methyl-D-aspartate (EC50 = 12 mu M), which was reversed by the group III mGluR antagonist (R,S)-alpha-methy lserine-O-phosphate but not by the group II antagonist (2S)-alpha-ethylglut amate. Moreover, (R,S)-PPG protected against N-methyl-D-aspariate- and quin olinic acid-induced striatal lesions in rats and was anticonvulsive in the maximal electroshock model in mice. In contrast to the group III mGluR agon ists L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate, (R,S)-PPG show ed no proconvulsive effects (2200 nmol i.c.v.). These data provide novel in vivo evidence for group III mGluRs as attractive targets for neuroprotecti ve and anticonvulsive therapy. Also, (R,S)-PPG represents an attractive too l to analyze the roles of group III mGluRs in nervous system physiology and pathology.