Summary
Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED50 s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i. v. and i. p. injection. Relative to CGP 37849, CGP 39551 was more potent after p. o. (ED50 3.7–8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED50 2.7–8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED50 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p. o. and above, and showed weak anticonvulsant activity against pentylenetetrazolevoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anticonvulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man.
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References
Baltzer V, Schmutz M (1978) Experimental anticonvulsant properties of GP 47680 and of GP 47779, its main human metabolite; compounds related to carbamazepine. In: Meinardi H, Rowan AJ (eds) Advances in epileptology: 9th epilepsy international symposium. Raven, New York, pp 295–299
Cavalheiro EA, Lehmann J, Turski L (eds) (1988) Frontiers in excitatory amino acid research. Liss, New York, pp 1–745
Cavalli-Sforza L (1972) Biometrie (Grundzüge biologisch-medizinischer Statistik). Fischer, Stuttgart, pp 1–212
Dingledine R, Hynes MA, King GL (1986) Involvement of N-methyl-d-aspartate receptors in epileptiform bursting in the rat hippocampal slice. J Physiol (Lond) 380:175–189
Fagg GE, Olpe HR, Bittiger H, Schmutz M, Angst C, Brundish D, Allgeier H, Heckendorn R, Dingwall JG (1988) CGP 37849/CGP 39551: potent and selective competitive NMDA receptor antagonists with oral activity. Soc Neurosci Abstr 14 (part 2):941
Fagg GE, Baud J, Pozza MF, Olpe HR, Schmutz M, Baumann P, Bittiger H, Allgeier H, Heckendorn R, Angst C, Brundish D, Dingwall JG (1990a) CGP 37849 and CGP 39551: novel and potent competitive N-methyl-d-aspartate receptor antagonists with oral activity. Br J Pharmacol (in press)
Fagg GE, Pozza MF, Schmutz M, Olpe HR, van Riezen H, Bittiger H, Angst C, Brundish D, Allgeier H, Heckendorn R, Dingwall JG (1990b) CGP 37849 and CGP 39551: novel competitive NMDA receptor antagonists with potent oral anticonvulsant activity. In: Williams M (ed) Current and future trends in anticonvulsant, anxiety and stroke therapy. Liss, New York (in press)
Flatman JA, Schwindt PC, Crill WE, Strafstrom CE (1983) Multiple actions of NMDA on cat neocortical neurones in vitro. Brain Res 266:169–173
France CP, Woods JH, Ornstein P (1989) The competitive NMDA antagonist CGS 19755 attenuates the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects. Eur J Pharmacol 159:133–139
Herrling PL, Morris R, Salt TE (1983) Effects of excitatory amino acids and their antagonists on membrane and action potentials of cat caudate neurones. J Physiol (Lond) 339:207–222
Herron CE, Williamson B, Collingridge GL (1985) A selective N-methyl-d-aspartate antagonist depresses epileptiform activity in rat hippocampal slices. Neurosci Lett 61:255–266
Lehmann J, Hutchison AJ, McPherson SE, Mondadori C, Schmutz M, Sinton CM, Tsai C, Murphy DE, Steel DJ, Williams M, Cheney DL, Wood PL (1988) CGS 19755, a selective and competitive N-methyl-d-aspartate-type excitatory amino acid receptor antagonist. J Pharmacol Exp Ther 246:65–75
Lodge D, Davies SN, Jones MG, Millar J, Manallack DT, Ornstein PL, Verberne AJM, Young N, Beart PM (1988) A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists. Br J Pharmacol 95:957–965
Meldrum BS (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68:113–122
Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B, White BG (1984) Antiepileptic drug development program. Cleve Clin Q 51:293–305
Pozza MF, Olpe HR, Brugger F, Fagg GE (1990) Electrophysiological characterization of a novel potent and orally active NMDA-receptor antagonist: CGP 37849 and its ethylester CGP 39551. Eur J Pharmacol (in press)
Racine RJ (1972) Modification of seizure activity by electrical stimulation: II. Motor seizure. EEG Clin Neurophysiol 32:281–294
Schmutz M (1985) Carbamazepine. In: Frey H-H, Janz D (eds) Antiepileptic drugs. Springer, Berlin Heidelberg New York, pp 479–506 (Handbook of experimental pharmacology, vol 74)
Schmutz M, Klebs K (1989) Kindling and antiepileptic drugs. In: Bolwig TG, Trimble MR (eds) The clinical relevance of kindling. Wiley, Chichester, pp 55–68
Schmutz M, Klebs K, Baltzer V (1988a) Inhibition or enhancement of kindling evolution by antiepileptics. J Neural Transm 72:245–257
Schmutz M, Klebs K, Olpe HR, Fagg GE, Allgeier H, Heckendorn R, Angst C, Brundish D, Dingwall JG (1988b) CGP 37849/CGP 39551: competitive NMDA receptor antagonists with potent oral anticonvulsant activity. Soc Neurosci Abstr 14 (part 2):864
Schmutz M, Bernasconi R, Portet C, Baltzer V (1989a) Effects of antiepileptic drugs in tests related to GABA. In: Manelis J, Cereghino JJ (eds) Advances in epileptology, vol 17. Raven, New York, pp 229–232
Schmutz M, Klebs K, Olpe HR, Allgeier H, Heckendorn R, Angst C, Brundish D, Dingwall JG, Fagg GE (1989b) CGP 37849/ CGP 39551: competitive NMDA receptor antagonists with potent oral anticonvulsant activity. Br J Pharmacol 97:581P
Schmutz M, Portet C, Olpe HR, Klebs K, Jeker A, Heckendorn R, Fagg GE, Allgeier H (1990) CGP 37849/CGP 39551: the first competitive NMDA receptor antagonists suitable for oral antiepileptic therapy. Exp Brain Res [Suppl] (in press)
Slater NT, Stelzer A, Galvan M (1985) Kindling-like stimulus pattern induce epileptiform discharges in the guinea pig in vitro hippocampus. Neurosci Lett 60:25–31
Watkins JC, Olverman HJ (1987) Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci 10:265–272
Wong EHF, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen L (1986) The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108
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Schmutz, M., Portet, C., Jeker, A. et al. The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents. Naunyn-Schmiedeberg's Arch Pharmacol 342, 61–66 (1990). https://doi.org/10.1007/BF00178973
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DOI: https://doi.org/10.1007/BF00178973