Midafotel

Midafotel

Clinical data
Other names	CPPene, Midafotel, SDZ EAA 494
ATC code	none
Pharmacokinetic data
Excretion	Renal
Identifiers
IUPAC name (R)-4-[(E)- 3-phosphonoprop- 2-enyl]piperazine- 2-carboxylic acid
CAS Number	117414-74-1  Y
PubChem CID	6437356
IUPHAR/BPS	4170
ChemSpider	4940497
UNII	7LYU6ZF84G
ChEBI	CHEBI:180900
CompTox Dashboard (EPA)	DTXSID001179674
Chemical and physical data
Formula	C8H15N2O5P
Molar mass	250.191 g·mol−1
3D model (JSmol)	Interactive image
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)

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]

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

• NMDA receptor antagonist

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.