Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893).

Abstract

The selective mGlu5 antagonists, MPEP, 2-methyl-6-phenylethynyl-pyridine, and SIB1893, (E)-6-methyl-2-styryl-pyridine, have been evaluated as antiepileptic drugs in DBA/2 mice and lethargic mice. Clonic seizures induced by the selective mGlu5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), 3 micromol intracerebroventricularly (i.c.v.), are potently suppressed by both compounds (MPEP, ED(50)=0.42 [0.28-0.62] mg/kg intraperitoneally (i.p.); SIB 1893 ED(50)=0.19 [0.11-0.33] mg/kg i.p. ). Clonic seizures induced by the mGlu1,5 agonist, 3, 5-dihydroxyphenylglycine (DHPG), 1.5 micromol i.c.v., are less potently suppressed by both compounds (MPEP, ED(50)=22 [13-38] mg/kg i.p., 110 [67-180] nmol i.c.v.; SIB1893, ED(50)=31 [18-54] mg/kg i.p. , 95 [82-110] nmol i.c.v.). Sound-induced seizures in DBA/2 mice are suppressed at 15 min by MPEP and SIB 1893 (MPEP ED(50) clonic seizures=18 [10-32] mg/kg i.p., 93 [69-125] nmol i.c.v.; tonic seizures=6.1 [4.5-8.3] mg/kg i.p., 46 [26-80] nmol i.c.v.; SIB 1893 ED(50) clonic seizures=27 [17-44] mg/kg i.p., 825 [615-1108] nmol i. c.v., tonic seizures=5.4 [3.4-8.6] mg/kg i.p., 194 [113-332] nmol i. c.v.). The ED(50) for MPEP for impaired rotarod performance is 128 [83-193] mg/kg i.p., at 15 min, i.e. a therapeutic index for sound-induced seizures of 5-20. In lethargic mice (lh/lh), a genetic absence model, MPEP, 50 mg/kg i.p., caused a marked reduction in the incidence of spontaneous spike-and-wave discharges. These selective antagonists of mGlu5 block seizures due to activation of mGlu5 at very low systemic doses. At rather higher doses they block convulsive and non-convulsive primary generalised seizures.

• Authors: A G Chapman, K Nanan, M Williams, B S Meldrum
• Journal: Neuropharmacology (Neuropharmacology) Vol. 39 Issue 9 Pg. 1567-74 (Jul 10 2000) ISSN: 0028-3908 [Print] England
• PMID: 10854901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Excitatory Amino Acid Antagonists
• Pyridines
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• Resorcinols
• SIB 1893
• 3,5-dihydroxyphenylglycine
• 6-methyl-2-(phenylethynyl)pyridine
• Glycine

Topics

• Animals
• Anticonvulsants (pharmacology)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (pharmacology)
• Female
• Glycine (adverse effects, analogs & derivatives)
• Injections, Intraperitoneal
• Injections, Intraventricular
• Male
• Mice
• Mice, Inbred DBA
• Pyridines (pharmacology)
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, metabolism)
• Resorcinols (adverse effects)
• Seizures (chemically induced, prevention & control)
• Sound (adverse effects)
• Time Factors