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
| Autor: | L. Singh, Linda J. Bristow, Paul D. Leeson, Brian John Williams, Peter H. Hutson, Mark D. Tricklebank, F. D. Tattersall, Michael Rowley, L. Thorn, K. L. Saywell |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Agonist medicine.drug_class Dopamine medicine.medical_treatment Phencyclidine Motor Activity Pharmacology Receptors N-Methyl-D-Aspartate Partial agonist Rats Sprague-Dawley Mice Receptors Glycine medicine Animals Pentylenetetrazol Behavior Animal Chemistry Pyrrolidinones Rats Anticonvulsant Mice Inbred DBA Glycine Convulsant NMDA receptor Anticonvulsants Dizocilpine Maleate Research Article medicine.drug |
| Zdroj: | British Journal of Pharmacology. 113:729-736 |
| ISSN: | 0007-1188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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