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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

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

L J Bristow, P H Hutson, J J Kulagowski, P D Leeson, S Matheson, F Murray, D Rathbone, K L Saywell, L Thorn, A P Watt, M D Tricklebank

J Pharmacol Exp Ther. 1996 Nov;279(2):492-501.

PMID: 8930150

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP142326598	L-701,324		142326-59-8	Price

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