The selective non-competitive
NMDA receptor antagonist,
MK-801, potently blocked convulsions induced in the mouse by
N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of
MK-801 were also effective in blocking
seizures induced by
pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive
NMDA receptor antagonists including
phencyclidine (PCP),
thienylcyclohexylpiperidine (TCP), (+)-
N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and
ketamine also blocked NMDLA-induced
seizures with a rank order of potency of
MK-801 greater than PCP greater than TCP = (+)-NANM greater than
ketamine. The competitive
NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-
phosphonic acid (
CPP) blocked NMDLA-induced
seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic
acid (2-APH) and 2-DL-amino-5-phosphonovaleric
acid (2-APV), respectively.
MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and
ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive
NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except
CPP, the
anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation:
CPP was 5- to 10-fold more potent as an
anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)