Two novel
N-methyl-D-aspartate (
NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic
acid CPG 37849 and the corresponding 1-ethyl
ester CGP 39551, were tested as
anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice,
CGP 37849 is more potent than
CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of
clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50
CGP 37849, 35.2 mumol/kg; ED50
CGP 39551, 28.1 mumol/kg). The time course of action of
CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against
clonic seizures for 48 h. Protection provided by other
NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic
acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic
acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic
acid 1-ethyl
ester 3 h, 4-(3-phosphonopropyl)-2-piperazine
carboxylic acid (
CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic
acid (
CGS 19755) 4 h, and
CGP 37849 4 h. After
oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and
anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (
CGP 37849) and 4.0-6.1 for 24 h (
CGP 39551). After i.p. administration, the TI values are
CGP 37849 at 1 h 2.4, and at 3 h 20.0,
CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of
CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced
myoclonus for at least 285 min, with severe side effects at the highest dose tested.
CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak
anticonvulsant activity only at the highest dose tested (accompanied by severe side effects).
CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced
myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of
seizures after 24 h. On the other hand,
CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of
anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)