{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:22Z","timestamp":1792789402757,"version":"4.5.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institutes of Health\/National Institute on Drug Abuse","award":["DA039143"],"award-info":[{"award-number":["DA039143"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Synthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nM affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low \u03bc\u039c affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to \u03949-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity\/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac024","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T12:31:24Z","timestamp":1645533084000},"page":"175-185","source":"Crossref","is-referenced-by-count":15,"title":["Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors"],"prefix":"10.1093","volume":"187","author":[{"given":"Christian V","family":"Cabanlong","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren N","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E","family":"Fantegrossi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3927-301X","authenticated-orcid":false,"given":"Paul L","family":"Prather","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences , Little Rock, Arkansas 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"2022062215233320500_kfac024-B1","doi-asserted-by":"crossref","first-page":"109960","DOI":"10.1016\/j.forsciint.2019.109960","article-title":"Identification of synthetic cannabinoids that were seized, consumed, or associated with deaths in Kuwait in 2018 using GC-MS and LC-MS-MS analysis","volume":"303","author":"Al-Matrouk","year":"2019","journal-title":"Forensic Sci. 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