1. The
anticonvulsant and behavioural effects of the
glycine/
NMDA receptor partial agonist,
L-687,414 (R(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one) have been investigated in rodents. 2.
L-687,414 dose-dependently antagonized
seizures induced by N-methyl-D,
L- aspartic acid (NMDLA, ED50 = 19.7 mg kg-1),
pentylenetetrazol (PTZ, ED50 = 13.0 mg kg-1) and electroshock (ED50 = 26.1 mg kg-1) when given intravenously 15 min before test, in male Swiss Webster mice but was most potent against audiogenic
seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg-1, i.
p., 30 min before test). 3.
L-687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:
anticonvulsant ED50] varied between 0.9 and 5, depending on the
convulsant used. 4. Similar behaviours to those seen after administration of the non-competitive
NMDA receptor antagonist,
MK-801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving
L-687,414, although the peak effect occurred at a dose (100 mg kg-1) which was 5-20 times the
anticonvulsant ED50S, depending on the
convulsant used. Unlike
MK-801, however, doses of
L-687,414 that were behaviourally stimulant did not increase
dopamine turnover in the nucleus accumbens. 5. Consistent with the interaction of
L-687,414 with the
glycine/
NMDA receptor, the
anticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the
glycine/
NMDA receptor agonist, D-
serine (10-100 micrograms per mouse, i.c.v.). 6. The results show that
L-687,414 is a potent, orally active
anticonvulsant with a more benign pharmacological profile than antagonists acting at the
ion channel of the
NMDA receptor complex. The compound is a useful tool with which to probe the functional role of the
glycine co-agonist site in vivo.