Pharmacological effects and pharmacokinetics of the novel synthetic cathinone α-pyrrolidinoisohexanophenone (α-PiHP) compared with α-pyrrolidinovalerophenone (α-PVP) in mice.

α-Pyrrolidinoisohexanophenone (α-PiHP) is a novel pyrovalerone cathinone that was among the top five synthetic cathinones seized by weight across Europe in 2022. Since α-PiHP was first reported to the European Union Drugs Agency in December 2016, its use has been linked to severe poisonings and fatalities. The present study employed in vitro and in vivo methods to evaluate the pharmacological effects and pharmacokinetics of α-PiHP in mice, using α-pyrrolidinovalerophenone (α-PVP) as a comparator drug. Our findings show that α-PiHP is a highly potent inhibitor of dopamine (DA) and norepinephrine (NE) reuptake, with a potency equivalent to that of α-PVP for the DA transporter (DAT) and slightly lower for the NE transporter (NET). The strong and targeted inhibition of DAT and NET indicates that α-PiHP has a high potential for misuse. In vivo studies showed that both drugs induced a significant increase in body temperature compared to the control, however, higher doses of α-PiHP (ED50: 4.0 mg/kg) were required to elicit locomotor activity compared to α-PVP (ED50: 1.1 mg/kg). Pharmacokinetic analyses revealed that α-PiHP reached approximately 40 % lower Cmax levels in blood and brain, which could explain the lower potency of α-PiHP in inducing locomotor activity. Overall, these findings highlight the need to evaluate the pharmacological characteristics of evolving synthetic cathinones, such as α-PiHP, to better understand the associated health risks.