The pharmacology of SDZ EAA 494, a competitive NMDA antagonist

• Published in: Neurochemistry international Vol. 25; no. 6; pp. 583 - 600
• Main Authors: Lowe, D.A., Emre, M., Frey, P., Kelly, P.H., Malanowski, J., McAllister, K.H., Neijt, H.C., Rüdeberg, C., Urwyler, S., White, T.G., Herring, P.L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.1994; Elsevier
• Subjects: Animals; Binding Sites; Biological and medical sciences; Cats; Corpus Striatum - drug effects; Dose-Response Relationship, Drug; Electroshock; Glutamatergic system (aspartate and other excitatory aminoacids); Kynurenic Acid; Medical sciences; Mice; N-Methylaspartate - antagonists & inhibitors; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nomifensine - pharmacology; Pharmacology. Drug treatments; Piperazines - antagonists & inhibitors; Piperazines - pharmacology; Rats; Rats, Sprague-Dawley; Sodium; Spinal Cord - drug effects; Vertebrata; trans-2,3-PDA; MK-801; PCP (phencyclidine); CPP; SDZ EAA 494 ( d-CPPene); CPPene; CGP 39653; trans-ACPD; Spinal cord; Rat; Frog; Rodentia; Central nervous system; Amphibia; Glutamate receptor; Salientia; Vertebrata; Mammalia; Animal; Antagonist; NMDA receptor; Brain (vertebrata)
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/0197-0186(94)90157-0

SDZ EAA 494 ( d-CPPene) was characterized as a competitive NMDA antagonist, having a p A 2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7–6.8 and a p K i 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 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 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.