LACK OF DEVELOPMENT OF TOLERANCE TO ANTICONVULSANT EFFECTS OF 2 EXCITATORY AMINO-ACID ANTAGONISTS, CFP-37849 AND CGP-39551 IN GENETICALLY EPILEPSY-PRONE RATS

Two selective excitatory amino acid antagonists, DL-(E)-2-amino-4-meth yl-5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551), were studied against audiogenic seizures in genetically e pilepsy-prone rats following oral administration. Acute administration of CGP 37849 attenuated the clonic and tonic phases of the audiogenic seizures (109 dB, 12-16 kHz) 120 min after pretreatment (ED(50) 19.7 and 11.2 mu mol kg(-1), respectively). Similarly, CGP 39551 attenuated the clonic and tonic phases of audiogenic seizures 120 min after acut e treatment with ED(50) values of 17.2 and 8.8 mu mol kg(-1), respecti vely. For chronic studies animals were treated orally once daily (at 1 0 h) for 4 weeks with CGP 37849 (20 or 40 mu mol kg(-1)) or CGP 39551 (15 or 30 mu mol kg(-1)). In order to assess anticonvulsant activity, rats were subjected to auditory stimulation 120 min after drug adminis tration on days 1, 3 and 5 and then every 3 or 4 days. Following 2 and 4 weeks of repeated drug administration with CGP 37849 (20 and 40 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were n ot significantly different from those observed following an acute admi nistration. Similarly, 2 and 3 weeks after repeated treatment CGP 3955 1 (15 and 30 mu mol kg(-1)) the ED(50) values against clonic and tonic seizures were not significantly different from those observed followi ng an acute administration. There was no significant difference betwee n the ED(50) values following either acute or repeated treatment of th e two excitatory amino acid antagonists suggesting a lack of developme nt tolerance. The duration of anticonvulsant activity observed between 0.5 and 24 h following administration of CGP 37849 and CGP 39551 was similar in acute and chronic treatment. The effects of CGP 37849 and C GP 39551 on motor behaviour was also evaluated following acute and rep eated treatment by a rotarod apparatus 110 min following drug administ ration. The TD50 values for CGP 37849- and CGP 39551-induced impairmen t of locomotor performance recorded 2 or 4 weeks of repeated administr ation were not significantly different from those observed following a n acute administration. The TD50 values for CGP 37849- and CGP 39551-i nduced impairment of locomotor performance were 87.6 and 70.8 mu mol k g(-1) i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mu mol kg(-1) i.p. respectively following 4 weeks treatment. The doses of CGP 37849 and CGP 39551 required to elicit motor impairment were a t least an order of magnitude above required for anticonvulsant activi ty, Since these compounds showed anticonvulsant properties after oral administration and lack of development of tolerance after repeated tre atment, a potential use for antiepileptic therapy in man is suggested.