title: Anticonvulsant and behavioral profile of L-701,324, a potent, orally active antagonist at the glycine modulatory site on the N-methyl-D-aspartate receptor complex.
abstract: The anticonvulsant and behavioral profile of the glycine/N-methyl-D-aspartate receptor antagonist L-701,324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinolone] has been examined in rodents. In mice, L-701,324 protected against seizures induced by N-methyl-DL-aspartate (ED50 = 3,4 mg/kg i.v.), pentylenetetrazol (ED50 = 2.8 mg/kg i.v.) and electroshock (ED50 = 1.4 mg/kg i.v.) but was most potent against audiogenic seizures in DBA/2 mice (ED50 = 0.96 mg/kg i.p.). L-701,324 was also active p.o. in mice (ED50 = 1.9,6.7, 20.7 and 34 mg/kg against audiogenic, electroshock-induced, N-methyl-DL-aspartate-induced and pentylenetetrazol-induced seizures, respectively) but showed weaker anticonvulsant activity in rats (ED50 = 90.5 mg/kg p.o., compared with 2.3 mg/kg i.v., against pentylenetetrazol-induced seizures), most probably because of the lower brain concentrations achieved in this species. Although anticonvulsant activity was also associated with impaired rotarod performance, L-701,324 failed to significantly increase locomotor activity or dopamine turnover in the nucleus accumbens at doses of up to 10 mg/kg i.v. in mice. Thus, in contrast to N-methyl-D-aspartate receptor ion channel blockers such as MK-801 (dizocilpine), L-701,324 is a potent, p.o. active anticonvulsant with a reduced propensity to activate mesolimbic dopaminergic systems in rodents.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bristow
authors.forename: P H
authors.initials: PH
authors.lastname: Hutson
authors.forename: J J
authors.initials: JJ
authors.lastname: Kulagowski
authors.forename: P D
authors.initials: PD
authors.lastname: Leeson
authors.forename: S
authors.initials: S
authors.lastname: Matheson
authors.forename: F
authors.initials: F
authors.lastname: Murray
authors.forename: D
authors.initials: D
authors.lastname: Rathbone
authors.forename: K L
authors.initials: KL
authors.lastname: Saywell
authors.forename: L
authors.initials: L
authors.lastname: Thorn
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: M D
authors.initials: MD
authors.lastname: Tricklebank
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C094635:L 701324; D004298:Dopamine