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)

• Published in: Neuropharmacology 2000-08, Vol.39 (9), p.1567-1574
• Main Authors: Chapman, Astrid G, Nanan, Karl, Williams, Martin, Meldrum, Brian S
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsant; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; CHPG; DBA/2 mice; DHPG; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - pharmacology; Female; Glutamate metabotropic receptor; Glutamatergic system (aspartate and other excitatory aminoacids); Glycine - adverse effects; Glycine - analogs & derivatives; Injections, Intraperitoneal; Injections, Intraventricular; Lethargic mice (lh/lh); Male; Medical sciences; mGlu5; Mice; Mice, Inbred DBA; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pyridines - pharmacology; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Resorcinols - adverse effects; Seizures - chemically induced; Seizures - prevention & control; Sound - adverse effects; Time Factors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(99)00242-7

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 μmol 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 μmol 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.