THE ANTICONVULSANT AND BEHAVIORAL PROFILE OF L-687,414, A PARTIAL AGONIST ACTING AT THE GLYCINE MODULATORY SITE ON THE N-METHYL-D-ASPARTATE(NMDA) RECEPTOR COMPLEX

1 The anticonvulsant and behavioural effects of the glycine/NMDA recep tor partial agonist, L-687,414 )-cis-beta-methyl-3-amino-1-hydroxypyrr olid-2-one) have been investigated in rodents. 2 L-687,414 dose-depend ently antagonized seizures induced by N-methyl-D,L-aspartic acid (NMDL A, ED(50) = 19.7 mg kg(-1)), pentylenetetrazol (PTZ, ED(50) = 13.0 mg kg(-1)) and electroshock (ED(50) = 26.1 mg kg(-1)) when given intraven ously 15 min before test, in male Swiss Webster mice but was most pote nt against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED(50) = 5.1 mg kg(-1), i.p., 30 min before test). 3 L-687,414 also i nduced impairments of performance in a rotarod test in both Swiss Webs ter and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED(50)] v aried between 0.9 and 5, depending on the convulsant used. 4 Similar b ehaviours to those seen after administration of the non-competitive NM DA receptor antagonist, MK-801 (head weaving, body rolling, hyperlocom otion) were seen in the mouse after giving L-687,414, although the pea k effect occurred at a dose (100 mg kg(-1)) which was 5-20 times the a nticonvulsant ED(50)s, depending on the convulsant used. Unlike MK-801 , however, doses of L-687,414 that were behaviourally stimulant did no t increase dopamine turnover in the nucleus accumbens. 5 Consistent wi th the interaction of L-687,414 with the glycine/NMDA receptor, the an ticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the glycine/NMDA receptor agonist, D-serin e (10-100 mu g per mouse, i.c.v.). 6 The results show that L-687,414 i s a potent, orally active anticonvulsant with a more benign pharmacolo gical profile than antagonists acting at the ion channel of the NMDA r eceptor complex. The compound is a useful tool with which to probe the functional role of the glycine co-agonist site in vivo.