ANTICONVULSANT ACTIVITY OF THE NMDA ANTAGONISTS, D(-)4-(3-PHOSPHONOPROPYL)PIPERAZINE-2-CARBOXYLIC ACID (D-CPP) AND D(-)(E)-4-(3-PHOSPHONOPROP-2-ENYL) PIPERAZINE-2-CARBOXYLIC ACID (D-CPPENE) IN A RODENT AND A PRIMATE MODEL OF REFLEX EPILEPSY

d-(-)4-(3-phosphonopropyl)piperazine-2-carboxylic acid (D-CPP) and its unsaturated analogue (d(-)(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (D-CPPene) have been administered to DBA/2 mice (intracerebroventricularly, i.c.v., intraperitoneally, i.p., and orally, p.o.) and to photosensitive baboons, Papio papio (intravenously, i.v., and orally), and their effects on reflexly induced epileptic responses assessed. In DBA/2 mice the clonic phase of the seizure response to sound is suppressed by D-CPP with an ED50 of 5.5 μg/mouse, i.c.v.; 0.69 mg (2.75 μmol)/kg i.p. and 16.6 mg (65.8 μmol)/kg p.o. compared with, for D-CPPene, 2.2 μg/mouse i.c.v., 0.41 mg (1.54 μmol)/kg i.p. and 10.8 mg (40.2 μmol)/kg, p.o. In Papio papio myoclonic responses to strobostopic stimulation are suppressed 24 and 48 h after D-CPP 32 mg (127 μmol)/kg p.o. Administration of D-CPPene 8-16 mg (30-60 μmol)/kg i.v. produces protection against myoclonic responses after 1-2 h, lasting for 48 h. Oral administration of D-CPPene 32-64 mg (119-239 μmol)/kg produces protection beginning after 4 h and sustained for 48 h. Measurements of plasma D-CPPene concentration show clearance after i.v. injection and a low plasma concentration 1.5-5 h after oral administration. The prolonged anticonvulsant action of D-CPP and D-CPPene following oral administration suggests that these compounds merit evaluation as antiepileptic therapy in man. © 1990.