CPPene

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IUPAC_name = (R)-4- [(E)-3-phosphonoprop-2-enyl] piperazine-2-carboxylic acid

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width = 240
CAS_number = 137424-80-7
synonyms = CPPene, Midafotel, SDZ EAA 494
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PubChem = 6437356
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C = 8 | H = 15 | N = 2 | O = 5 | P = 1
molecular_weight = 250.189 g/mol
smiles = C1CN(CC(N1)C(=O)O)CC=CP(=O)(O)O
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excretion = Renal
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CPPene (Midafotel, SDZ EAA 494) is a potent competitive antagonist at the NMDA receptor. [Lowe DA, Neijt HC, Aebischer B. D-CPP-ene (SDZ EAA 494), a potent and competitive N-methyl-D-aspartate (NMDA) antagonist: effect on spontaneous activity and NMDA-induced depolarizations in the rat neocortical slice preparation, compared with other CPP derivatives and MK-801. "Neuroscience Letters". 1990 Jun 8;113(3):315-21. PMID 2166255] It was originally designed as a potential therapy for excitotoxicity, [Bullock R, McCulloch J, Graham DI, Lowe D, Chen MH, Teasdale GM. Focal ischemic damage is reduced by CPP-ene studies in two animal models. "Stroke". 1990 Nov;21(11 Suppl):III32-6. PMID 2146780] epilepsy or neuropathic pain. [Bespalov A, Kudryashova M, Zvartau E. Prolongation of morphine analgesia by competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494) in rats. "European Journal of Pharmacology". 1998 Jun 26;351(3):299-305. PMID 9721021] It looked very promising in "in vitro" trials proving to be a potent competitive antagonist at the NMDA without affecting other receptors. [Lowe DA, Emre M, Frey P, Kelly PH, Malanowski J, McAllister KH, Neijt HC, Rüdeberg C, Urwyler S, White TG, et al. The pharmacology of SDZ EAA 494, a competitive NMDA antagonist. "Neurochemistry International". 1994 Dec;25(6):583-600. PMID 7894335] Research continued through to "in vitro" tissue culture studies where it proved to limit damage after occluding the middle cerebral artery leading to ischaemia. It also blocked photosensitive epilepsies in baboons. [Patel S, Chapman AG, Graham JL, Meldrum BS, Frey P. Anticonvulsant activity of the NMDA antagonists, D(-)4-(3-phosphonopropyl) piperazine-2-carboxylic acid (D-CPP) and D(-)(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (D-CPPene) in a rodent and a primate model of reflex epilepsy. "Epilepsy Research". 1990 Sep-Oct;7(1):3-10. PMID 2292244]

CPPene had a pharmacokinetic profile suitable for progressing to clinical trials as it has no toxic by products, is excreted exclusively via the renal system and remains unchanged in the brain.

However CPPene was removed from clinical trials as it provided no suitable neuronal protection or beneficial treatment for epilepsy, [Sveinbjornsdottir S, Sander JW, Upton D, Thompson PJ, Patsalos PN, Hirt D, Emre M, Lowe D, Duncan JS. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. "Epilepsy Research". 1993 Oct;16(2):165-74. PMID 8269915] and had side effects which led to many patients withdrawing from trials. [Rockstroh S, Emre M, Tarral A, Pokorny R. Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans. "Psychopharmacology (Berlin)". 1996 Apr;124(3):261-6. PMID 8740048] A possible explanation for its lack of efficacy in trials is the relatively short therapeutic time window following ischaemic damage and the fact that a small amount of glutamate helps neuronal survival. It is also believed that some "pro-survival" genes are activated by NMDA receptors.

References