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These compounds are mainly active through their potent agonism on the cannabinoid receptors CB\n 1<\/jats:sub>\n and CB\n 2<\/jats:sub>\n . Recently, evidence of the direct interaction of some SCRAs with the serotonergic 5\u2010HT receptors has emerged.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n SCRAs were screened for in vitro 5\u2010HT\n 2A<\/jats:sub>\n receptor activity using AequoScreen\u00ae intracellular Ca\n 2+<\/jats:sup>\n release and inositol monophosphate (IP\n 1<\/jats:sub>\n ) formation assays. The pharmaco\u2010toxicological effects induced by the administration of the most effective compound in vitro (AB\u20105\u2032F\u2010BUTINACA) were investigated in male CD\u20101 mice with specific focus on its interaction with CB\n 1<\/jats:sub>\n and 5\u2010HT\n 2A<\/jats:sub>\n receptors.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Many SCRAs with a valinamide (AB) or\n tert<\/jats:italic>\n \u2010leucinamide (ADB) head moiety had in vitro activity at the 5\u2010HT\n 2A<\/jats:sub>\n receptor at high concentrations with AB\u20105\u2032F\u2010BUTINACA and ADB\u2010BUTINACA amongst the most efficacious. In vivo studies showed that AB\u20105\u2032F\u2010BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduction in breath rate and hypolocomotion in mice. The neurological, sensorimotor, and thermal antinociceptive effects were mediated by CB\n 1<\/jats:sub>\n and 5\u2010HT\n 2A<\/jats:sub>\n receptors, as they were prevented by pretreatment with the selective CB\n 1<\/jats:sub>\n and 5\u2010HT\n 2A<\/jats:sub>\n receptor antagonists (NESS0327 and MDL100907, respectively).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and Implications<\/jats:title>\n \n This study demonstrated for the first time that SCRAs with a valinamide or\n tert<\/jats:italic>\n \u2010leucinamide head moiety activate the 5\u2010HT\n 2A<\/jats:sub>\n receptor. Agonism of the compound AB\u20105\u2032F\u2010BUTINACA at the 5\u2010HT\n 2A<\/jats:sub>\n receptors resulted in in vivo effects. Our data revealed potential risks related to SCRA consumption that could exacerbate unexpected psychiatric conditions.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.70457","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T02:50:43Z","timestamp":1778035843000},"page":"4715-4734","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["5\u2010HT\n 2A<\/sub>\n receptor agonism by\n tert<\/i>\n \u2010leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-2446","authenticated-orcid":false,"given":"Giorgia","family":"Corli","sequence":"first","affiliation":[{"name":"Department of Excellence of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine University of Ferrara Ferrara 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