Comprehensive in vitro profiling of traditional and emerging stimulants at monoamine transporters and the 5-HT2A receptor.
Darta Stalberga, Robert Kronstrand, Bianca Schranz, Nick Van Zijl, Sebastian Karlman, Soma Aref, Tobias Rautio, Svante Vikingsson, Mattias Persson, Henrik Gréen
British Journal of Pharmacology July 14, 2026 DOI: 10.1111/bph.70587 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Topics | Serotonin |
| Keywords | 5‐ht2a receptor Monoamine transporters Neurotransmitter uptake inhibitors New psychoactive substances Synthetic cathinones |
| Key points | N-pyrrolidine cathinones with methylenedioxy groups showed the highest potency at the dopamine transporter, and most tested synthetic cathinones suggest high abuse potential based on DAT/SERT selectivity. |
Abstract
New psychoactive substances (NPSs) often emerge on the illicit drug market with limited pharmacological or toxicological data. Synthetic cathinones are the second largest NPS group, often mimicking the effects of classical stimulants such as cocaine and methylenedioxymethamphetamine (MDMA). Such stimulants primarily target dopamine (DAT), norepinephrine (NET) and serotonin (SERT) transporters, with DAT selectivity being linked to abuse potential. Owing to the lack of pharmacological profiling, this study aimed to determine the potencies and structure-activity relationships (SARs) of recently emerged stimulants. Employing in vitro human transporter inhibition assay and AequoScreen® 5-HT2A receptor activity assay, the potency, transporter selectivity, DAT/SERT, DAT/NET, and NET/SERT ratios, and group-wide SARs of 58 substances were investigated. Most synthetic cathinones inhibited DAT at nanomolar concentrations, with N-pyrrolidine cathinones in combination with methylenedioxy groups-4-methylenedioxy-α-pyrrolidino-isohexanophenone (MDPiHP), 3,4-methylenedioxy PV8 (MDPEP), and 3,4-methylenedioxy pyrovalerone (MDPV)-demonstrating the highest DAT potency among all the tested stimulants. In contrast, other N-pyrrolidine cathinones, 3F-α-PHP, 3F-α-PiHP and 4F-α-PiHP, exhibited the highest DAT selectivity (DAT/SERT ratio). Chloromethcathinone (CMC) and methylmethcathinone (MMC) compounds, such as 3-CMC, exhibited a distinct amphetamine-like pharmacological uptake inhibition profile showing a comparable potency between DAT and NET. Some cathinones at high concentrations and phenethylamines in micromolar concentrations additionally activated the 5-HT2A receptor, whereas 2C-like arylcyclohexylamines primarily targeted the receptor without transporter inhibition. These results show that cathinones displayed distinct group SARs. Based on the DAT/SERT selectivity, the majority of the investigated compounds, especially N-pyrrolidine cathinones, suggest a high abuse potential.