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Vol. 289, Issue 3, 1678-1687, June 1999

(R,S)-4-Phosphonophenylglycine, a Potent and Selective Group III Metabotropic Glutamate Receptor Agonist, Is Anticonvulsive and Neuroprotective In Vivo

F. Gasparini, V. Bruno, G. Battaglia, S. Lukic, T. Leonhardt, W. Inderbitzin, D. Laurie, B. Sommer, M. A. Varney, S. D. Hess, E. C. Johnson, R. Kuhn, S. Urwyler, D. Sauer, C. Portet, M. Schmutz, F. Nicoletti and P. J. Flor

Novartis Pharma AG, Nervous System Research, Basel, Switzerland (F.G., S.L., T.L., W.I., D.L., B.S., R.K., S.U., D.S., C.P., M.S., P.J.F.); Istituto Mediterraneo di Neuroscienze "Neuromed," Pozzilli, Italy (V.B., G.B., F.N.); SIBIA Neurosciences Incorporated, La Jolla, California (M.A.V., S.D.H., E.C.J.); and University of Catania, Catania, Italy (F.N.)

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 human N-methyl-D-aspartate, alpha -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--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 (EC50 = 12 µM), which was reversed by the group III mGluR antagonist (R,S)-alpha -methylserine-O-phosphate but not by the group II antagonist (2S)-alpha -ethylglutamate. Moreover, (R,S)-PPG protected against N-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 and L-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.

0022-3565/99/2893-1678$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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