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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.

Abstract
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.
AuthorsM D Tricklebank, L J Bristow, P H Hutson, P D Leeson, M Rowley, K Saywell, L Singh, F D Tattersall, L Thorn, B J Williams
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 113 Issue 3 Pg. 729-36 (Nov 1994) ISSN: 0007-1188 [Print] England
PMID7858861 (Publication Type: Journal Article)
Chemical References
  • Anticonvulsants
  • Pyrrolidinones
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate
  • L 687414
  • Dizocilpine Maleate
  • Phencyclidine
  • Dopamine
Topics
  • Animals
  • Anticonvulsants (pharmacology)
  • Behavior, Animal (drug effects)
  • Dizocilpine Maleate (pharmacology)
  • Dopamine (metabolism)
  • Male
  • Mice
  • Mice, Inbred DBA
  • Motor Activity (drug effects)
  • Phencyclidine (pharmacology)
  • Pyrrolidinones (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glycine (agonists)
  • Receptors, N-Methyl-D-Aspartate (agonists, antagonists & inhibitors)

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