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

✍ Scribed by Smita Patel; Astrid G. Chapman; Joanne L. Graham; Brian S. Meldrum; Peter Frey

• Publisher: Elsevier Science
• Year: 1990
• Tongue: English
• Weight: 775 KB
• Volume: 7
• Category: Article
• ISSN: 0920-1211
• DOI: 10.1016/0920-1211(90)90049-2

✦ Synopsis

D.(-)4.(3-phosphonopropyl)piperazine-2-carboxylic acid (D-CPP) and its unsaturated analogue (D(-)(E).4-(3.phosphonoprop-2enyl) 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, Papiopapio (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 El~0 of 5,5 ~g/mouse. i.c.v.; 0.69 mg (2.75 #mol)/kg i.p. and 16.6 mg (65.8 #moi)/kg p.o. compared with, for D.CPPene, 2.2 gg/mouse i.c.v., 0.41 mg (1..54 #mol)/kg i.p. and 10.8 mg (40.2#mol)/kg, p.o.

In Papio papio myoclonic responses to strobos 3pic stimulation are suppressed 24 and 48 h after D-CPP 32 mg (127 #moi)/kg p.o. Administration of D-CPPene 8-16 mg (30-60 #mol)/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/~mol)/kg produces protection beginning after 4 h and sustained for 48 h. Measurements of plasma D-CPPene concenuation show rapid 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.