Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 Nov;113(3):729–736. doi: 10.1111/j.1476-5381.1994.tb17054.x

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.

M D Tricklebank 1, L J Bristow 1, P H Hutson 1, P D Leeson 1, M Rowley 1, K Saywell 1, L Singh 1, F D Tattersall 1, L Thorn 1, B J Williams 1
PMCID: PMC1510413  PMID: 7858861

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.).(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
729

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anis N. A., Berry S. C., Burton N. R., Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983 Jun;79(2):565–575. doi: 10.1111/j.1476-5381.1983.tb11031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bristow L. J., Hutson P. H., Thorn L., Tricklebank M. D. The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents. Br J Pharmacol. 1993 Apr;108(4):1156–1163. doi: 10.1111/j.1476-5381.1993.tb13520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Criswell H. E., Johnson K. B., Mueller R. A., Breese G. R. Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats. J Pharmacol Exp Ther. 1993 May;265(2):1001–1010. [PubMed] [Google Scholar]
  4. Davies J., Evans R. H., Herrling P. L., Jones A. W., Olverman H. J., Pook P., Watkins J. C. CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]D-AP5 binding sites on brain membranes and anticonvulsant activity. Brain Res. 1986 Sep 10;382(1):169–173. doi: 10.1016/0006-8993(86)90127-7. [DOI] [PubMed] [Google Scholar]
  5. French E. D., Vantini G. Phencyclidine-induced locomotor activity in the rat is blocked by 6-hydroxydopamine lesion of the nucleus accumbens: comparisons to other psychomotor stimulants. Psychopharmacology (Berl) 1984;82(1-2):83–88. doi: 10.1007/BF00426386. [DOI] [PubMed] [Google Scholar]
  6. Hargreaves R. J., Rigby M., Smith D., Hill R. G. Lack of effect of L-687,414 ((+)-cis-4-methyl-HA-966), an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology. Br J Pharmacol. 1993 Sep;110(1):36–42. doi: 10.1111/j.1476-5381.1993.tb13768.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hutson P. H., Bristow L. J., Thorn L., Tricklebank M. D. R-(+)-HA-966, a glycine/NMDA receptor antagonist, selectively blocks the activation of the mesolimbic dopamine system by amphetamine. Br J Pharmacol. 1991 Aug;103(4):2037–2044. doi: 10.1111/j.1476-5381.1991.tb12372.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kemp J. A., Foster A. C., Leeson P. D., Priestley T., Tridgett R., Iversen L. L., Woodruff G. N. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6547–6550. doi: 10.1073/pnas.85.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Koek W., Colpaert F. C. Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther. 1990 Jan;252(1):349–357. [PubMed] [Google Scholar]
  10. Koek W., Woods J. H., Colpaert F. C. N-methyl-D-aspartate antagonism and phencyclidine-like activity: a drug discrimination analysis. J Pharmacol Exp Ther. 1990 Jun;253(3):1017–1025. [PubMed] [Google Scholar]
  11. Monyer H., Sprengel R., Schoepfer R., Herb A., Higuchi M., Lomeli H., Burnashev N., Sakmann B., Seeburg P. H. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science. 1992 May 22;256(5060):1217–1221. doi: 10.1126/science.256.5060.1217. [DOI] [PubMed] [Google Scholar]
  12. Moriyoshi K., Masu M., Ishii T., Shigemoto R., Mizuno N., Nakanishi S. Molecular cloning and characterization of the rat NMDA receptor. Nature. 1991 Nov 7;354(6348):31–37. doi: 10.1038/354031a0. [DOI] [PubMed] [Google Scholar]
  13. Rao T. S., Kim H. S., Lehmann J., Martin L. L., Wood P. L. Selective activation of dopaminergic pathways in the mesocortex by compounds that act at the phencyclidine (PCP) binding site: tentative evidence for PCP recognition sites not coupled to N-methyl-D-aspartate (NMDA) receptors. Neuropharmacology. 1990 Mar;29(3):225–230. doi: 10.1016/0028-3908(90)90005-c. [DOI] [PubMed] [Google Scholar]
  14. Rowley M., Leeson P. D., Stevenson G. I., Moseley A. M., Stansfield I., Sanderson I., Robinson L., Baker R., Kemp J. A., Marshall G. R. 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically active anticonvulsants acting by antagonism at the glycine site of the N-methyl-D-aspartate receptor complex. J Med Chem. 1993 Oct 29;36(22):3386–3396. doi: 10.1021/jm00074a020. [DOI] [PubMed] [Google Scholar]
  15. Singh L., Donald A. E., Foster A. C., Hutson P. H., Iversen L. L., Iversen S. D., Kemp J. A., Leeson P. D., Marshall G. R., Oles R. J. Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative. Proc Natl Acad Sci U S A. 1990 Jan;87(1):347–351. doi: 10.1073/pnas.87.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Singh L., Menzies R., Tricklebank M. D. The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor. Eur J Pharmacol. 1990 Sep 4;186(1):129–132. doi: 10.1016/0014-2999(90)94069-a. [DOI] [PubMed] [Google Scholar]
  17. Singh L., Wong E. H., Kesingland A. C., Tricklebank M. D. Evidence against an involvement of the haloperidol-sensitive sigma recognition site in the discriminative stimulus properties of (+)-N-allylnormetazocine ((+)-SKF 10,047). Br J Pharmacol. 1990 Jan;99(1):145–151. doi: 10.1111/j.1476-5381.1990.tb14668.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Smith S. E., Meldrum B. S. The glycine-site NMDA receptor antagonist, R-(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one, L-687,414 is anticonvulsant in baboons. Eur J Pharmacol. 1992 Jan 28;211(1):109–111. doi: 10.1016/0014-2999(92)90270-e. [DOI] [PubMed] [Google Scholar]
  19. Svensson A., Pileblad E., Carlsson M. A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice. J Neural Transm Gen Sect. 1991;85(2):117–129. doi: 10.1007/BF01244704. [DOI] [PubMed] [Google Scholar]
  20. Tiedtke P. I., Bischoff C., Schmidt W. J. MK-801-induced stereotypy and its antagonism by neuroleptic drugs. J Neural Transm Gen Sect. 1990;81(3):173–182. doi: 10.1007/BF01245040. [DOI] [PubMed] [Google Scholar]
  21. Tricklebank M. D., Singh L., Oles R. J., Preston C., Iversen S. D. The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol. 1989 Aug 11;167(1):127–135. doi: 10.1016/0014-2999(89)90754-1. [DOI] [PubMed] [Google Scholar]
  22. Tricklebank M. D., Singh L., Oles R. J., Wong E. H., Iversen S. D. A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencyclidine. Eur J Pharmacol. 1987 Sep 23;141(3):497–501. doi: 10.1016/0014-2999(87)90573-5. [DOI] [PubMed] [Google Scholar]
  23. Willetts J., Balster R. L. Effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists in rats trained to discriminate NMDA from saline. J Pharmacol Exp Ther. 1989 Nov;251(2):627–633. [PubMed] [Google Scholar]
  24. Willetts J., Balster R. L., Leander J. D. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci. 1990 Oct;11(10):423–428. doi: 10.1016/0165-6147(90)90150-7. [DOI] [PubMed] [Google Scholar]
  25. Williams K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993 Oct;44(4):851–859. [PubMed] [Google Scholar]
  26. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES