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Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5\u2010HT<jats:sub>2A<\/jats:sub> receptors (5\u2010HT<jats:sub>2A<\/jats:sub>R) and muscarinic M<jats:sub>1<\/jats:sub> receptors (M<jats:sub>1<\/jats:sub>R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M<jats:sub>1<\/jats:sub>R (minimal displacement of [~<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>] [<jats:sup>3<\/jats:sup>H]scopolamine up to 10\u00a0\u03bcM). However, two SCs, \u03b1\u2010pyrrolidinopropiophenone (\u03b1\u2010PPP) and 4\u2010methyl\u2010\u03b1\u2010PPP, had low \u03bcM <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values at 5\u2010HT<jats:sub>2A<\/jats:sub>R. In 5\u2010HT<jats:sub>2A<\/jats:sub>R\u2013phosphoinositide hydrolysis assays, \u03b1\u2010PPP and 4\u2010methyl\u2010\u03b1\u2010PPP displayed inverse agonist activity. We further assessed the 5\u2010HT<jats:sub>2A<\/jats:sub>R functional activity of \u03b1\u2010PPP, and observed it competitively antagonized 5\u2010HT<jats:sub>2A<\/jats:sub>R signaling stimulated by the 5\u2010HT<jats:sub>2<\/jats:sub>R agonist (\u00b1)\u20102,5\u2010dimethoxy\u20104\u2010iodoamphetamine (DOI; <jats:italic>K<\/jats:italic><jats:sub>b<\/jats:sub>\u00a0=\u00a0851\u00a0nM). To assess in vivo 5\u2010HT<jats:sub>2A<\/jats:sub>R activity, we examined the effects of \u03b1\u2010PPP on the DOI\u2010elicited head\u2010twitch response (HTR) in mice. \u03b1\u2010PPP dose\u2010dependently blocked the HTR with maximal suppression at 10\u00a0mg\/kg (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), which is a moderate dose used in studies investigating psychostimulant properties of \u03b1\u2010PPP. To corroborate a 5\u2010HT<jats:sub>2A<\/jats:sub>R mechanism, we also tested 3,4\u2010methylenedioxy\u2010\u03b1\u2010PPP (MDPPP) and 3\u2010bromomethcathinone (3\u2010BMC), SCs that we observed had 5\u2010HT<jats:sub>2A<\/jats:sub>R <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>s\u00a0&gt;\u00a010\u00a0\u03bcM. Neither MDPPP nor 3\u2010BMC, at 10\u00a0mg\/kg doses, attenuated the DOI HTR. Our results suggest \u03b1\u2010PPP has antagonist interactions at 5\u2010HT<jats:sub>2A<\/jats:sub>R in vitro that may translate at physiologically\u2010relevant doses in vivo. Considering 5\u2010HT<jats:sub>2A<\/jats:sub>R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to \u03b1\u2010PPPs unpopularity compared to other monoamine transporter inhibitors.<\/jats:p>","DOI":"10.1002\/dta.2582","type":"journal-article","created":{"date-parts":[[2019,3,7]],"date-time":"2019-03-07T14:05:34Z","timestamp":1551967534000},"page":"990-998","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The synthetic cathinone psychostimulant \u03b1\u2010PPP antagonizes serotonin 5\u2010HT<sub>2A<\/sub> receptors: In vitro and in vivo evidence"],"prefix":"10.1002","volume":"11","author":[{"given":"Yiming","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Mercer University  Atlanta GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce 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