NFEPP
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| Other names | 3-Fluorofentanyl |
| Drug class | Opioid |
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| Chemical and physical data | |
| Formula | C22H27FN2O |
| Molar mass | 354.469 g·mol−1 |
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NFEPP (N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenylpropionamide) is an analgesic opioid chemical, similar in structure to fentanyl, designed in 2016 by Spahn et al. from Free University of Berlin[2] to avoid the standard negative side effects of opiates, including opioid overdose, by only targeting inflamed tissue.[3][4]
Pharmacology
Computer models suggest fentanyl binds to μ-opioid receptors in its protonated form. Fluorination of fentanyl at the 3-position lowers the pKa of its conjugate acid from 8.4 to 6.8, a change designed to reduce its systemic effects while maintaining its potency in inflamed tissue, as this is a more acidic environment (pH 5–7) than non-inflamed tissue (pH 7.4).[4][5]
In experiments on rats with different types of inflammatory pain, it has been shown that NFEPP produces injury-restricted analgesia, while exhibiting reduced typical opiate effects such as respiratory depression, sedation, constipation, and chemical seeking behavior.[6][7][8]
As a result, NFEPP has the potential to reduce opioid addiction and dependency, as there is no effect on users who are not actually suffering from pain, as the chemical does not interact with non-inflamed brain tissue until much higher doses are reached.[9]
Further research indicates other fluorinated derivatives of fentanyl, such as β-fluorofentanyl (FF3) or 2'-fluoro β-fluorofentanyl (RR-49), may be more effective in achieving high potency in damaged tissue with low potency in undamaged tissue.[4][10]
See also
References
- ^ Drug Enforcement Administration Do (February 2018). "Schedules of Controlled Substances:Temporary Placement of Fentanyl-Related Substances in Schedule I. Temporary amendment; temporary scheduling order". Federal Register. 83 (25): 5188–92. PMID 29932611.
- ^ Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N, Temp J, et al. (March 2017). "A nontoxic pain killer designed by modeling of pathological receptor conformations". Science. 355 (6328): 966–969. Bibcode:2017Sci...355..966S. doi:10.1126/science.aai8636. PMID 28254944. S2CID 206653322.
- ^ Halford B (2017). "An opioid minus major side effects". Chemical & Engineering News. 95 (10): 8.
- ^ a b c Edwards SR, Blough BE, Cowart K, Howell GH, Araujo AA, Haskell JP, et al. (May 2024). "Assessment of the Antinociceptive, Respiratory-Depressant, and Reinforcing Effects of the Low pKa Fluorinated Fentanyl Analogs, FF3 and NFEPP". Neuropharmacology. 255 110002. doi:10.1016/j.neuropharm.2024.110002. PMC 11195011. PMID 38754577.
- ^ Mole B (4 March 2017). "Early study suggests new opioid is non-addictive, works only where it hurt". Ars Technica.
- ^ Rodriguez-Gaztelumendi A, Spahn V, Labuz D, Machelska H, Stein C (November 2018). "Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain". Pain. 159 (11): 2277–2284. doi:10.1097/j.pain.0000000000001328. PMC 6203420. PMID 29994988.
- ^ Massaly N, Temp J, Machelska H, Stein C (December 2020). "Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain". Pain. 161 (12): 2798–2804. doi:10.1097/j.pain.0000000000001968. PMID 32639370. S2CID 220410251.
- ^ Degro CE, Jiménez-Vargas NN, Tsang Q, Yu Y, Guzman-Rodriguez M, Alizadeh E, et al. (June 2023). "Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid". Pain. 164 (11): 2501–2515. doi:10.1097/j.pain.0000000000002956. PMC 10731875. PMID 37326658.
- ^ Baamonde A, Menéndez L, González-Rodríguez S, Lastra A, Seitz V, Stein C, et al. (October 2020). "A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors". Scientific Reports. 10 (1) 18599. Bibcode:2020NatSR..1018599B. doi:10.1038/s41598-020-75509-4. PMC 7596718. PMID 33122720.
- ^ Rosas R, Huang XP, Roth BL, Dockendorff C (September 2019). "β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists". ACS Medicinal Chemistry Letters. 10 (9): 1353–1356. doi:10.1021/acsmedchemlett.9b00335. PMC 6746189. PMID 31531209.