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.

Abstract

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 micrograms/mouse, i.c.v.; 0.69 mg (2.75 mumol)/kg i.p. and 16.6 mg (65.8 mumol)/kg p.o. compared with, for D-CPPene, 2.2 micrograms/mouse i.c.v., 0.41 mg (1.54 mumol)/kg i.p. and 10.8 mg (40.2 mumol)/kg, p.o. In Papio papio myoclonic responses to stroboscopic stimulation are suppressed 24 and 48 h after D-CPP 32 mg (127 mumol)/kg p.o. Administration of D-CPPene 8-16 mg (30-60 mumol)/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 mumol)/kg produces protection beginning after 4 h and sustained for 48 h. Measurements of plasma D-CPPene concentration 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.

• Authors: S Patel, A G Chapman, J L Graham, B S Meldrum, P Frey
• Journal: Epilepsy research (Epilepsy Res) 1990 Sep-Oct Vol. 7 Issue 1 Pg. 3-10 ISSN: 0920-1211 [Print] Netherlands
• PMID: 2292244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Organophosphorus Compounds
• Piperazines
• SDZ EAA 494
• N-Methylaspartate
• 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid

Topics

• Acoustic Stimulation
• Animals
• Anticonvulsants (pharmacology)
• Epilepsy (physiopathology)
• Male
• Mice
• Mice, Inbred Strains
• N-Methylaspartate (antagonists & inhibitors)
• Organophosphorus Compounds (blood, pharmacology)
• Papio
• Photic Stimulation
• Piperazines (blood, pharmacology)
• Rotation