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Competitive NMDA receptor antagonists raise electrically kindled generalized seizure thresholds

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Abstract

A sensitive method of estimation of generalized seizure thresholds (GSTs) was used to estimate the relative anticonvulsant potencies of four competitive NMDA antagonists against fully amygdala-kindled seizures. All of the antagonists tested showed potent, dose-dependent anticonvulsant activity following focal administration at doses causing no, or only minimal, overt behavioural abnormalities. These doses were similar to those which have previously been shown to inhibit the development of the kindling process i.e. which show antiepileptogenic activity. Two novel, competitive NMDA antagonists, CGP 37849 and CGP 39551, both unsaturated analogues of the NMDA antagonist AP5, showed by far the greatest anticonvulsant potencies (211-fold and 33-fold greater activity than the parent molecule, respectively). Recent reports of oral anticonvulsant activity of these two compounds in both rodent and primate models of epilepsy (12, 13) make them leading candidates for clinical testing as novel antiepileptic agents in man. Previous reports of weak or non-existent anticonvulsant activity of competitive NMDA antagonists in the kindling model of epilepsy most likely result from the use of experimental protocols which are inherently insensitive in detecting drug-induced changes in seizure thresholds.

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Authors and Affiliations

  1. Department of Biochemistry, Imperial College of Science, Technology and Medicine, Imperial College Road, Kensinton, SW7 2AZ, London, UK

    Katie L. Cotterell & Henry F. Bradford

  2. Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, WC1N 1AX, London, UK

    Martin J. Croucher

Authors
  1. Martin J. Croucher
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  2. Katie L. Cotterell
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  3. Henry F. Bradford
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Special issue dedicated to Dr. Morris H. Aprison.

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Croucher, M.J., Cotterell, K.L. & Bradford, H.F. Competitive NMDA receptor antagonists raise electrically kindled generalized seizure thresholds. Neurochem Res 17, 409–413 (1992). https://doi.org/10.1007/BF00969885

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