Two selective
excitatory amino acid antagonists, DL-(E)-2-amino-4-methyl- 5-phosphono-3-pentenoic
acid (
CGP 37849) and its carboxyethylester (
CGP 39551), were studied against audiogenic
seizures in genetically
epilepsy-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 (ED50 19.7 and 11.2 mumol kg-1, respectively). Similarly,
CGP 39551 attenuated the clonic and tonic phases of audiogenic
seizures 120 min after acute treatment with ED50 values of 17.2 and 8.8 mumol kg-1, respectively. For chronic studies animals were treated orally once daily (
at 10 h) for 4 weeks with
CGP 37849 (20 or 40 mumol kg-1) or
CGP 39551 (15 or 30 mumol kg-1). In order to assess
anticonvulsant activity, rats were subjected to auditory stimulation 120 min after
drug administration 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 mumol kg-1) the ED50 values against clonic and
tonic seizures were not significantly different from those observed following an acute administration. Similarly, 2 and 4 weeks after repeated treatment
CGP 39551 (15 and 30 mumol kg-1) the ED50 values against clonic and
tonic seizures were not significantly different from those observed following an acute administration. There was no significant difference between the ED50 values following either acute or repeated treatment of the two
excitatory amino acid antagonists suggesting a lack of development 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
CGP 39551 on motor behaviour was also evaluated following acute and repeated treatment by a rotarod apparatus 110 min following
drug administration. The TD50 values for
CGP 37849 and CGP 39551-induced impairment of locomotor performance recorded 2 or 4 weeks of repeated administration were not significantly different from those observed following an acute administration. The TD50 values for
CGP 37849- and CGP 39551-induced impairment of locomotor performance were 87.6 and 70.8 mumol kg-1 i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mumol kg-1 i.p. respectively following 4 weeks treatment. The doses of
CGP 37849 and
CGP 39551 required to elicit motor impairment were at least an order of magnitude above required for
anticonvulsant activity. Since these compounds showed
anticonvulsant properties after
oral administration and lack of development of tolerance after repeated treatment, a potential use for
antiepileptic therapy in man is suggested.