Midafotel

Midafotel (CPPene; SDZ EAA 494) is a potent, competitive antagonist at the NMDA receptor.[1] It was originally designed as a potential therapy for excitotoxicity,[2] epilepsy or neuropathic pain.[3] It looked very promising in in vitro trials proving to be a potent competitive antagonist at the NMDA without affecting other receptors.[4] Research continued through to in vivo cat studies where it proved to limit damage after occluding the middle cerebral artery, leading to ischaemia. It also blocked photosensitive epilepsies in baboons.[5]

Midafotel
Clinical data
Other namesCPPene, Midafotel, SDZ EAA 494
ATC code
  • none
Pharmacokinetic data
ExcretionRenal
Identifiers
IUPAC name
  • (R)-4-[(E)- 3-phosphonoprop- 2-enyl]piperazine- 2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
Chemical and physical data
FormulaC8H15N2O5P
Molar mass250.191 g·mol−1
3D model (JSmol)
SMILES
  • C1CN(C[C@@H](N1)C(=O)O)C/C=C/P(=O)(O)O
InChI
  • InChI=1S/C8H15N2O5P/c11-8(12)7-6-10(4-2-9-7)3-1-5-16(13,14)15/h1,5,7,9H,2-4,6H2,(H,11,12)(H2,13,14,15)/b5-1+/t7-/m1/s1
  • Key:VZXMZMJSGLFKQI-ABVWVHJUSA-N
  (verify)

CPPene had a pharmacokinetic profile suitable for progressing to clinical trials, as it has no toxic byproducts, 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,[6] and had side effects which led to many patients withdrawing from trials.[7] 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.

See also

References
  1. Lowe DA, Neijt HC, Aebischer B (June 1990). "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. 113 (3): 315–21. doi:10.1016/0304-3940(90)90604-8. PMID 2166255. S2CID 26349391.
  2. Bullock R, McCulloch J, Graham DI, Lowe D, Chen MH, Teasdale GM (November 1990). "Focal ischemic damage is reduced by CPP-ene studies in two animal models". Stroke. 21 (11 Suppl): III32-6. PMID 2146780.
  3. Bespalov A, Kudryashova M, Zvartau E (June 1998). "Prolongation of morphine analgesia by competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494) in rats". European Journal of Pharmacology. 351 (3): 299–305. doi:10.1016/s0014-2999(98)00324-0. PMID 9721021.
  4. Lowe DA, Emre M, Frey P, Kelly PH, Malanowski J, McAllister KH, et al. (December 1994). "The pharmacology of SDZ EAA 494, a competitive NMDA antagonist". Neurochemistry International. 25 (6): 583–600. doi:10.1016/0197-0186(94)90157-0. PMID 7894335. S2CID 24530990.
  5. Patel S, Chapman AG, Graham JL, Meldrum BS, Frey P (1990). "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. 7 (1): 3–10. doi:10.1016/0920-1211(90)90049-2. PMID 2292244. S2CID 5765562.
  6. Sveinbjornsdottir S, Sander JW, Upton D, Thompson PJ, Patsalos PN, Hirt D, et al. (October 1993). "The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy". Epilepsy Research. 16 (2): 165–74. doi:10.1016/0920-1211(93)90031-2. PMID 8269915. S2CID 42473190.
  7. Rockstroh S, Emre M, Tarral A, Pokorny R (April 1996). "Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans". Psychopharmacology. 124 (3): 261–6. doi:10.1007/bf02246666. PMID 8740048. S2CID 36727794.
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