PT  - JOURNAL ARTICLE
AU  - Bristow, L J
AU  - Hutson, P H
AU  - Kulagowski, J J
AU  - Leeson, P D
AU  - Matheson, S
AU  - Murray, F
AU  - Rathbone, D
AU  - Saywell, K L
AU  - Thorn, L
AU  - Watt, A P
AU  - Tricklebank, M D
TI  - 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.
DP  - 1996 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 492--501
VI  - 279
IP  - 2
4099  - http://jpet.aspetjournals.org/content/279/2/492.short
4100  - http://jpet.aspetjournals.org/content/279/2/492.full
SO  - J Pharmacol Exp Ther1996 Nov 01; 279
AB  - 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.