title: The pharmacology of SDZ EAA 494, a competitive NMDA antagonist.
abstract: SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 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 acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with 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-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.
authors.affiliation: Sandoz Research Institute Bern Ltd., Switzerland.
authors.forename: D A
authors.initials: DA
authors.lastname: Lowe
authors.forename: M
authors.initials: M
authors.lastname: Emre
authors.forename: P
authors.initials: P
authors.lastname: Frey
authors.forename: P H
authors.initials: PH
authors.lastname: Kelly
authors.forename: J
authors.initials: J
authors.lastname: Malanowski
authors.forename: K H
authors.initials: KH
authors.lastname: McAllister
authors.forename: H C
authors.initials: HC
authors.lastname: Neijt
authors.forename: C
authors.initials: C
authors.lastname: Rüdeberg
authors.forename: S
authors.initials: S
authors.lastname: Urwyler
authors.forename: T G
authors.initials: TG
authors.lastname: White
mesh_terms: D000818:Animals; D001665:Binding Sites; D002415:Cats; D003342:Corpus Striatum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007736:Kynurenic Acid; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009627:Nomifensine / Q000494:pharmacology; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D010879:Piperazines; C065286:SDZ EAA 494; D009627:Nomifensine; D016202:N-Methylaspartate; D012964:Sodium; D007736:Kynurenic Acid