Abstract

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, EC₅₀ 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 EC₅₀ and IC₅₀ values of ≥200 μM at group I and II hmGluRs and was inactive at cloned humanN-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate, and kainate receptors (>300 μM). On the other hand, it showed micromolar affinity for a Ca²⁺/Cl⁻-dependentl-glutamate binding site in rat brain, similar to other phosphono-substituted amino acids likel-2-amino-4-phosphonobutyrate. In cultured cortical neurons, (R,S)-PPG provided protection against a toxic pulse ofN-methyl-d-aspartate (EC₅₀ = 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 againstN-methyl-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 andl-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.