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Here we characterize the analytical quantification, clinical presentation, and pharmacological mechanism of action for <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone. Liquid chromatography coupled to tandem mass spectrometry (LC\u2013MS\/MS) was used to quantify <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone in blood obtained from human cases. Clinical features exhibited by the intoxicated individuals are described. The activity of <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone at plasma membrane transporters for dopamine (DAT), norepinephrine (NET) and 5\u2010HT (SERT) was assessed using in vitro assays measuring uptake inhibition and evoked release of [<jats:sup>3<\/jats:sup>H] neurotransmitters in rat brain synaptosomes. Our LC\u2013MS\/MS method assayed <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone concentrations with limits of detection and quantification of 1 and 5\u00a0ng\/mL, respectively. Quantitation was linear from 5 to 500\u00a0ng\/mL, and the method displayed specificity and reproducibility. Circulating concentrations of <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone ranged from 7 to 170\u00a0ng\/mL in clinical cases, and the associated symptoms included palpitations, tachycardia, agitation, hallucinations, coma and death. <jats:italic>N\u2010<\/jats:italic>Ethylnorpentylone was a potent inhibitor at DAT (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a037\u00a0nM), NET (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a0105\u00a0nM) and SERT (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a0383\u00a0nM) but displayed no transporter releasing activity. We present a validated method for quantifying <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone in human case work. The drug is a psychomotor stimulant capable of inducing serious cardiovascular and neurological side\u2010effects which can be fatal. In vitro findings indicate that <jats:italic>N<\/jats:italic>\u2010ethylnorpentylone exerts its effects by potent blockade of DAT and NET, thereby elevating extracellular levels of dopamine and norepinephrine in the brain and periphery.<\/jats:p>","DOI":"10.1002\/dta.2502","type":"journal-article","created":{"date-parts":[[2018,9,11]],"date-time":"2018-09-11T20:19:31Z","timestamp":1536697171000},"page":"461-471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Analytical quantification, intoxication case series, and pharmacological mechanism of action for <i>N<\/i>\u2010ethylnorpentylone (<i>N<\/i>\u2010ethylpentylone or ephylone)"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-3391","authenticated-orcid":false,"given":"Jose Luiz","family":"Costa","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences University of Campinas  Campinas S\u00e3o Paulo 13083\u2010859 Brazil"},{"name":"Campinas Poison Control Center, Faculty of Medical Sciences University of Campinas  Campinas S\u00e3o Paulo 13083\u2010859 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8078-3356","authenticated-orcid":false,"given":"Kelly Francisco","family":"Cunha","sequence":"additional","affiliation":[{"name":"Campinas Poison Control Center, Faculty of Medical Sciences University of Campinas  Campinas S\u00e3o Paulo 13083\u2010859 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-0974","authenticated-orcid":false,"given":"Rafael","family":"Lanaro","sequence":"additional","affiliation":[{"name":"Campinas Poison Control Center, Faculty of Medical Sciences University of Campinas  Campinas S\u00e3o Paulo 13083\u2010859 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0444-7742","authenticated-orcid":false,"given":"Ricardo Leal","family":"Cunha","sequence":"additional","affiliation":[{"name":"Institute of Chemistry Federal University of Bahia  Salvador Bahia 40170\u2010115 Brazil"},{"name":"Institute of Analysis and Forensic Research  Aracaju Sergipe 49100\u2010000 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Walther","sequence":"additional","affiliation":[{"name":"Designer Drug Research Unit of the Intramural Research Program National Institute on Drug Abuse (NIDA), National Institutes of Health  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Baumann","sequence":"additional","affiliation":[{"name":"Designer Drug Research Unit of the Intramural Research Program National Institute on Drug Abuse (NIDA), National Institutes of Health  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2016_34"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3223-14.2014"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.204"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X13666141210225009"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000263"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/1556-4029.12260"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkt001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3109\/00952990.2011.643999"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.forsciint.2017.12.003"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02145.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.304"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2013.10.029"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2016_53"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.116.236349"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-015-4057-0"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13640"},{"key":"e_1_2_8_18_1","unstructured":"Drug Enforcement Administration (DEA).Emerging threat report (mid\u2010year).https:\/\/ndews.umd.edu\/sites\/ndews.umd.edu\/files\/dea\u2010emerging\u2010threat\u2010report\u20102017\u2010mid\u2010year.pdf. 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