THE PHARMACOLOGY OF SDZ-EAA-494, A COMPETITIVE NMDA ANTAGONIST

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagon ist, having a pA(2) value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pK(i) of 7.5 in a [H-3]CGP3965 3 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models w ith an ED(50) of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisi tion of a passive avoidance task, suggesting potential effects on memo ry formation, occurred at supra-anticonvulsant doses in rodents. with PCP-like stimulatory effects produced only by high i.p. doses or const ant i.v. infusions. This favourable profile is discussed in relation t o the negative outcome of a recent trial of the compound in patients w ith intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-isch aemic action of SDZ EAA 494 encourages further testing in brain trauma , in which the anticonvulsant action of the compound may be an added b enefit.