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

LJ Bristow, PH Hutson, JJ Kulagowski, PD Leeson, S Matheson, F Murray, D Rathbone, KL Saywell, L Thorn, AP Watt and MD Tricklebank

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.

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.

Volume 279, Issue 2, pp. 492-501, 11/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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