The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT 2A receptors: In vitro and in vivo evidence

Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. 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‐HT(2A) receptors (5‐HT(2A)R) and muscarinic M(1) receptors (M(1)R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M(1)R (minimal displacement of [~K(d)] [3H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K(i) values at 5‐HT(2A)R. In 5‐HT(2A)R–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT(2A)R functional activity of α‐PPP, and observed it competitively antagonized 5‐HT(2A)R signaling stimulated by the 5‐HT(2)R agonist (±)‐2,5‐ dimethoxy‐4‐iodoamphetamine (DOI; K(b) = 851 nM). To assess in vivo 5‐HT(2A)R activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppressiont 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT(2A)R mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT(2A)R K(i)s > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT(2A)R in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT(2A)R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.