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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 pentylenetetrazol-evoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anti-convulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man.

I The effects of bilateral olfactory bulbectomy, sham-operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability. 2 Bulbectomized rats were hyperactive, deficient at learning a step-down passive avoidance response and hyperirritable. Peripheral anosmia, induced by intranasal infusion of ZnSO4 solution resulted in no behavioural changes. 3 Chronic pretreatment with amitriptyline (3 and 10mg/kg) and a tetracyclic antidepressant mianserin (Org GB 94, 5 and 15 mg/kg) reversed the hyperactivity and reduced the learning deficit of bulbectomized rats. These drugs had no significant effects on sham-operated animals. 4 Neither amitriptyline nor mianserin reduced the exaggerated responses of bulbectomized rats to external stimuli. 5(+)-Amphetamine (1 and 3 mg/kg) accelerated the acquisition of the passive avoidance response, greatly enhanced the locomotor activity and slightly increased the irritability score of both shamoperated and bulbectomized rats. 6 Chlorpromazine (1 and 3 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the acquisition, locomotor activity and irritability of experimental and control rats. 7 Lithium sulphate (1 and 3 mg/kg) had no effect on activity or irritability but produced a small impairment in acquisition of bulbectomized rats. 8 It is concluded that the reversal by antidepressant drugs of the behavioural syndrome seen after olfactory bulb ablation could constitute a new model for the detection of this group of centrally acting compounds.