title: (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo.
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 microM, 4.7 +/- 0.9 microM, 185 +/- 42 microM, and 0.2 +/- 0.1 microM, respectively, were measured. The compound showed EC50 and IC50 values of >/=200 microM 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 microM). 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 microM), 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.
authors.affiliation: Novartis Pharma AG, Nervous System Research, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
authors.forename: V
authors.initials: V
authors.lastname: Bruno
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: S
authors.initials: S
authors.lastname: Lukic
authors.forename: T
authors.initials: T
authors.lastname: Leonhardt
authors.forename: W
authors.initials: W
authors.lastname: Inderbitzin
authors.forename: D
authors.initials: D
authors.lastname: Laurie
authors.forename: B
authors.initials: B
authors.lastname: Sommer
authors.forename: M A
authors.initials: MA
authors.lastname: Varney
authors.forename: S D
authors.initials: SD
authors.lastname: Hess
authors.forename: E C
authors.initials: EC
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: S
authors.initials: S
authors.lastname: Urwyler
authors.forename: D
authors.initials: D
authors.lastname: Sauer
authors.forename: C
authors.initials: C
authors.lastname: Portet
authors.forename: M
authors.initials: M
authors.lastname: Schmutz
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.forename: P J
authors.initials: PJ
authors.lastname: Flor
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004597:Electroshock; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists; D015290:Second Messenger Systems / Q000187:drug effects; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: C119327:4-phosphonophenylglycine; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D010716:Phosphatidylinositols; D020033:Protein Isoforms; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D005576:Colforsin; D018698:Glutamic Acid; D016202:N-Methylaspartate; D000242:Cyclic AMP; D017378:Quinolinic Acid; D005998:Glycine