NFEPP
{{Short description|Opioid analgesic drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Use dmy dates|date=March 2017}}
{{drugbox
| IUPAC_name = N-(3-Fluoro-1-phenethylpiperidin-4-yl)-N-phenylpropionamide
| image = Nfepp.png
| image_class = skin-invert-image
| C=22 | H=27 | F=1 | N=2 | O=1
| ChemSpiderID = 58826238
| CAS_number = 1422952-84-8
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = NXR38LA4PA
| SMILES = CCC(=O)N(c1ccccc1)[C@H]2CCN(C[C@H]2F)CCc3ccccc3
| StdInChI = 1S/C22H27FN2O/c1-2-22(26)25(19-11-7-4-8-12-19)21-14-16-24(17-20(21)23)15-13-18-9-5-3-6-10-18/h3-12,20-21H,2,13-17H2,1H3/t20-,21+/m1/s1
| StdInChIKey = DMCQJJAWMFBPOX-RTWAWAEBSA-N
| class = Opioid
| legal_US = Schedule I{{cite journal | title = Schedules of Controlled Substances:Temporary Placement of Fentanyl-Related Substances in Schedule I. Temporary amendment; temporary scheduling order | journal = Federal Register | volume = 83 | issue = 25 | pages = 5188–92 | date = February 2018 | pmid = 29932611 | last1 = Drug Enforcement Administration | first1 = Department of Justice }}
}}
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{{cite journal | vauthors = Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N, Temp J, Durmaz V, Sabri P, Reidelbach M, Machelska H, Weber M, Stein C | title = A nontoxic pain killer designed by modeling of pathological receptor conformations | journal = Science | volume = 355 | issue = 6328 | pages = 966–969 | date = March 2017 | pmid = 28254944 | doi = 10.1126/science.aai8636 | bibcode = 2017Sci...355..966S | s2cid = 206653322 }} to avoid the standard negative side effects of opiates, including opioid overdose, by only targeting inflamed tissue.{{cite journal | vauthors = Halford B |url=http://cen.acs.org/articles/95/i10/opioid-minus-major-side-effects.html | title = An opioid minus major side effects | journal = Chemical & Engineering News | volume = 95 | issue = 10 | page = 8 | date = 2017}}{{cite journal | vauthors = Edwards SR, Blough BE, Cowart K, Howell GH, Araujo AA, Haskell JP, Huskinson SL, Rowlett JK, Brackeen MF, Freeman KB | title = Assessment of the Antinociceptive, Respiratory-Depressant, and Reinforcing Effects of the Low pKa Fluorinated Fentanyl Analogs, FF3 and NFEPP | journal = Neuropharmacology | volume = 255| issue = | pages = 110002 | date = May 2024 | pmid = 38754577 | doi = 10.1016/j.neuropharm.2024.110002 | pmc = 11195011 | pmc-embargo-date = September 1, 2025 }}
Inflamed tissue
Inflamed tissue has a lower pH value (~5–7) than non-inflamed tissue (7.4).{{cite web | first = Beth | last = Mole | url=https://arstechnica.com/science/2017/03/tweaking-fentanyls-chemical-structure-may-create-safer-opioid/ | title=Early study suggests new opioid is non-addictive, works only where it hurt | publisher = Ars Technica | date = March 4, 2017}} Through computer simulation, scientists found a way to make the fentanyl analog only affect inflamed tissue via the addition of fluorine to the chemical structure. In experiment, it was shown that NFEPP produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting typical opiate effects, including respiratory depression, sedation, constipation, and chemical seeking behavior.{{cite journal | vauthors = Rodriguez-Gaztelumendi A, Spahn V, Labuz D, Machelska H, Stein C | title = Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain | journal = Pain | volume = 159 | issue = 11 | pages = 2277–2284 | date = November 2018 | pmid = 29994988 | doi = 10.1097/j.pain.0000000000001328 | pmc = 6203420 }}{{cite journal | vauthors = Massaly N, Temp J, Machelska H, Stein C | title = Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain | journal = Pain | volume = 161 | issue = 12 | pages = 2798–2804 | date = December 2020 | pmid = 32639370 | doi = 10.1097/j.pain.0000000000001968 | s2cid = 220410251 }}{{cite journal | vauthors = Degro CE, Jiménez-Vargas NN, Tsang Q, Yu Y, Guzman-Rodriguez M, Alizadeh E, Hurlbut D, Reed DE, Lomax AE, Stein C, Bunnett NW, Vanner SJ | title = Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid | journal = Pain | volume = 164| issue = 11| date = June 2023 | pages = 2501–2515 | pmid = 37326658 | doi = 10.1097/j.pain.0000000000002956 | pmc = 10731875 }}
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.{{cite journal | vauthors = Baamonde A, Menéndez L, González-Rodríguez S, Lastra A, Seitz V, Stein C, Machelska H | title = A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 18599 | date = October 2020 | pmid = 33122720 | doi = 10.1038/s41598-020-75509-4 | pmc = 7596718 | bibcode = 2020NatSR..1018599B | doi-access = free }}