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

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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 mechanismsof presynaptic inhibition, such as regulation of neurotransmitterrelease. 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 $>=$ 200µM at group I and II hmGluRs and was inactive at cloned humanN-methyl-D-aspartate, $alpha$ -amino-3-hydroxy-5-methyl-isoxazole-4-propionate,and kainate receptors (>300 µM). On the other hand, it showedmicromolar affinity for a Ca²⁺/Cl-dependent L-glutamate binding site in rat brain, similar to otherphosphono-substituted amino acids like L-2-amino-4-phosphonobutyrate.In cultured cortical neurons, (R,S)-PPG provided protection againsta toxic pulse of N-methyl-D-aspartate (EC₅₀ = 12 µM), which wasreversed by the group III mGluR antagonist (R,S)- $alpha$ -methylserine-O-phosphatebut not by the group II antagonist (2S)- $alpha$ -ethylglutamate. Moreover,(R,S)-PPG protected against N-methyl-D-aspartate- and quinolinicacid-induced striatal lesions in rats and was anticonvulsive inthe maximal electroshock model in mice. In contrast to the groupIII 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 mGluRsas attractive targets for neuroprotective and anticonvulsive therapy.Also, (R,S)-PPG represents an attractive tool to analyze the rolesof group III mGluRs in nervous system physiology andpathology.

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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