Anticonvulsant activity of a metabotropic glutamate receptor 8 preferential agonist, (R,S)-4-phosphonophenylglycine.
Agonists at group III glutamate metabotropic receptors, such as L-serine-O-phosphate, have pro- and anti-convulsant activities in rodent models. We have used intracerebroventricular administration to test a novel group III agonist, (R,S)-4-phosphonophenylglycine (PPG), that is preferential for mglu(8), against sound-induced seizures in DBA/2 mice. Tonic and clonic seizures are abolished at 15 min (ED(50s) 0.14 [0.04-0.4] nmol, and 3.4 [2.1-5.6] nmol, respectively). The protection against tonic and clonic seizures by 20 nmol PPG is complete for 4 h, diminished by 6 h, and absent by 10 h. In contrast, L-Serine-O-phosphate gives only partial protection against sound-induced clonic seizures for 15-30 min (ED(50) 79 [45-139] nmol) in DBA/2 mice. In genetically epilepsy prone rats sound-induced seizures were blocked 5-60 min after the bilateral administration of PPG, 5-10 nmol, into the inferior colliculus. These data suggest that the mglu(8) receptor is a potential target for novel antiepileptic drugs.
Chapman
A G
AG
Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London, UK. spgtagc@iop.kcl.ac.uk
Nanan
K
K
Yip
P
P
Meldrum
B S
BS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007245:Inferior Colliculi / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010768:Phosphoserine / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D013016:Sound / Q000009:adverse effects; D013997:Time Factors
C119327:4-phosphonophenylglycine; D000927:Anticonvulsants; D018094:Receptors, Metabotropic Glutamate; C111435:metabotropic glutamate receptor 8; D010768:Phosphoserine; D005998:Glycine