The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents.
Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED50s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i.v. and i.p. injection. Relative to CGP 37849, CGP 39551 was more potent after p.o. (ED50 3.7-8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED50 2.7-8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED50 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p.o. and above, and showed weak anticonvulsant activity against pentylenetetrazol-evoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anti-convulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man.
Schmutz
M
M
Research and Development Department, CIBA-GEIGY Ltd., Basel, Switzerland.
Portet
C
C
Jeker
A
A
Klebs
K
K
Vassout
A
A
Allgeier
H
H
Heckendorn
R
R
Fagg
G E
GE
Olpe
H R
HR
van Riezen
H
H
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants; D004597:Electroshock; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C064540:CGP 39551; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D015763:2-Amino-5-phosphonovalerate; D010433:Pentylenetetrazole