The anticonvulsant and behavioural 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 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.
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
M D
MD
Tricklebank
L J
LJ
Bristow
P H
PH
Hutson
P D
PD
Leeson
M
M
Rowley
K
K
Saywell
L
L
Singh
F D
FD
Tattersall
L
L
Thorn
B J
BJ
Williams
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors
D000927:Anticonvulsants; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C084173:L 687414; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D004298:Dopamine