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Since the comprehensive scheduling of fentanyl analogues in many countries worldwide, several non-fentanyl NSOs have emerged on the illicit drug market, increasing the risks of addiction and fatal overdoses. Dipyanone, a methadone-like NSO, was first identified in drug seizures in 2021 and later also in postmortem cases. This study aimed to assess the metabolism of dipyanone in humans using in silico predictions, in vitro human hepatocyte incubations, and authentic urine specimens. Dipyanone was primarily metabolised through the opening of the pyrrolidine ring to form the corresponding <jats:italic>N<\/jats:italic>-butan-4-ol or <jats:italic>N<\/jats:italic>-butanoic acid compound, followed by cyclisation to 4\u2019-[2-ethylidene-5-methyl-3,3-diphenylpyrrolidin-1-yl]butan-1\u2019-ol (EMDPB) and 4\u2019-[2-ethylidene-5-methyl-3,3-diphenylpyrrolidin-1-yl]butanoic acid (EMDPBA); other metabolic transformations included hydroxylation, reduction, and <jats:italic>O<\/jats:italic>-glucuronidation. We propose EMDPB and EMDPBA as specific biomarkers of dipyanone consumption. Additionally, dipyanone\u2019s activation of \u00b5- (MOR), \u03ba- (KOR), and \u03b4- (DOR) opioid receptors was evaluated with a homogeneous time-resolved fluorescence-based GTP G<jats:sub>i<\/jats:sub> binding assay. The half-maximal effective concentration (EC<jats:sub>50<\/jats:sub>) and maximum effect (<jats:italic>E<\/jats:italic>\n            <jats:sub>max<\/jats:sub>) were 96.8\u00a0nM and 106% (compared to fentanyl at MOR), 380.4\u00a0nM and 13% (compared to U-50488 at KOR), and 1067\u00a0nM and 56% (compared to SNC-80 at DOR). Dipyanone\u2019s opioid receptor activation pattern was similar to that of methadone, with a strong agonistic effect at MOR, potentially inducing potent analgesic effects with health risks through the central nervous system and respiratory depression, as well as an abuse and dependence potential. Further pharmacokinetic and pharmacodynamic studies should be conducted to better understand the toxicological relevance of dipyanone.<\/jats:p>","DOI":"10.1007\/s00204-025-04023-1","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T22:47:12Z","timestamp":1745880432000},"page":"2339-2353","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dipyanone, a new methadone-like synthetic opioid: In vitro and in vivo human metabolism and pharmacological profiling"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3005-5825","authenticated-orcid":false,"given":"Diletta","family":"Berardinelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-9312","authenticated-orcid":false,"given":"Johannes","family":"Kutzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0633-2117","authenticated-orcid":false,"given":"Omayema","family":"Taoussi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-7139","authenticated-orcid":false,"given":"Simona","family":"Zaami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6347-0750","authenticated-orcid":false,"given":"Simona","family":"Pichini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-4223","authenticated-orcid":false,"given":"Giuseppe","family":"Basile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3082-4532","authenticated-orcid":false,"given":"Francesco Paolo","family":"Busard\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1883-2804","authenticated-orcid":false,"given":"Volker","family":"Auw\u00e4rter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-9518","authenticated-orcid":false,"given":"Jeremy","family":"Carlier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"4023_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/J.FORSCIINT.2020.110553","volume":"317","author":"A \u00c5strand","year":"2020","unstructured":"\u00c5strand A, Guerrieri D, Vikingsson S, Kronstrand R, Green H (2020) In vitro characterization of new psychoactive substances at the \u03bc-opioid, CB1, 5HT1A, and 5-HT2A receptors\u2014On-target receptor potency and efficacy, and off-target effects. 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