title: (S)-4-carboxy-3-hydroxyphenylglycine, an antagonist of metabotropic glutamate receptor (mGluR) 1a and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 mice.
abstract: The in vivo anticonvulsant effects and in vitro metabotropic glutamate receptor selectivity of (S)-4-carboxy-3-hydroxy-phenylglycine [(S)-4C3HPG] were examined. Intracerebroventricular injection of (S)-4C3HPG dose-dependently antagonized audiogenic-induced clonic and tonic convulsions in DBA/2 mice with ED50 values of 76 and 110-nmol per mouse, respectively. (S)-4C3HPG dose-dependently inhibited the spontaneously evoked epileptic spikes in a cingulate cortex-corpus callosum slice preparation. (S)-4C3HPG displaced the binding of [3H]glutamate in membranes prepared from baby hamster kidney (BHK) cells expressing the metabotropic glutamate receptor mGluR1a with an EC50 of 5 +/- 1 microM. (S)-4C3HPG dose-dependently antagonized glutamate-stimulated phosphoinositide hydrolysis in BHK cells expressing mGluR1a with an IC50 of 15 +/- 3 microM. (S)-4C3HPG was, however, an agonist at mGluR2 with an EC50 of 21 +/- 4 microM for inhibition of forskolin-stimulated cyclic AMP formation in BHK cells expressing the mGluR2. (S)-4C3HPG had no effects at mGluR4a. These data suggest that the anticonvulsant action of (S)-4C3HPG is mediated by combined antagonism of mGluR1a and agonism of mGluR2. These results suggest the importance of mGluR1a and/or mGluR2 in the control of epileptic activity.
authors.affiliation: Department of Receptor Neurochemistry, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: H
authors.initials: H
authors.lastname: Klitgaard
authors.forename: M
authors.initials: M
authors.lastname: Sheardown
authors.forename: H C
authors.initials: HC
authors.lastname: Jackson
authors.forename: K
authors.initials: K
authors.lastname: Eskesen
authors.forename: P
authors.initials: P
authors.lastname: Jacobsen
authors.forename: S
authors.initials: S
authors.lastname: Treppendahl
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D018094:Receptors, Metabotropic Glutamate; C078245:4-carboxy-3-hydroxyphenylglycine; D005998:Glycine