RT Journal Article
SR Electronic
T1 (R,S)-4-Phosphonophenylglycine, a Potent and Selective Group III Metabotropic Glutamate Receptor Agonist, Is Anticonvulsive and Neuroprotective In Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1678
OP 1687
VO 289
IS 3
A1 F. Gasparini
A1 V. Bruno
A1 G. Battaglia
A1 S. Lukic
A1 T. Leonhardt
A1 W. Inderbitzin
A1 D. Laurie
A1 B. Sommer
A1 M. A. Varney
A1 S. D. Hess
A1 E. C. Johnson
A1 R. Kuhn
A1 S. Urwyler
A1 D. Sauer
A1 C. Portet
A1 M. Schmutz
A1 F. Nicoletti
A1 P. J. Flor
YR 1999
UL http://jpet.aspetjournals.org/content/289/3/1678.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics