The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents

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 ED50s 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.