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

The anticonvulsant and behavioral profile of the glycine/N-methyl-D-as partate receptor antagonist L-701,324 hloro-4-hydroxy-3-(3-phenoxy)phe nyl-2(H)quinolone] has been examined in rodents. In mice, L-701,324 pr otected against seizures induced by N-methyi-DL-aspartate (ED(50) = 3. 4 mg/kg i.v.), pentylenetetrazol (ED(50) = 2.8 mg/kg i.v.) and electro shock (ED(50) = 1.4 mg/kg i.v.) but was most potent against audiogenic seizures in DBA/2 mice (ED(50) = 0.96 mg/kg i.p.). L-701,324 was also active p.o. in mice (ED(50) = 1.9, 6.7, 20.7 and 34 mg/kg against aud iogenic, electroshock-induced, N-methyl-DL-aspartate-induced and penty lenetetrazol-induced seizures, respectively) but showed weaker anticon vulsant activity in rats (ED(50) = 90.5 mg/kg p.o., compared with 2.3 mg/kg i.v., against penlylenetetrazol-induced seizures), most probably because of the lower brain concentrations achieved in this species. a lthough anticonvulsant activity was also associated with impaired rota rod performance, L-701,324 failed to significantly increase locomotor activity or dopamine turnover in the nucleus accumbens at doses ct up to 10 mg/kg i.v. in mice. Thus, in contrast to N-methyl-D-aspartate re ceptor ion channel blockers such as MK-801 (dizocilpine), L-701,324 is a potent, p.o. active anticonvulsant with a reduced propensity to act ivate mesolimbic dopaminergic systems in rodents.