New synthetic drugs show cocaine-like potency, complicating law enforcement
Researchers have mapped how emerging street drugs bind to brain receptors with surprising strength—some rivaling cocaine's addictive potential. The findings could help regulators and treatment providers anticipate harms from novel substances before they spread widely.
Originaltitel: Comprehensive in vitro profiling of traditional and emerging stimulants at monoamine transporters and the 5-HT
Nya syntetiska katinoner på illegal marknad uppvisar högre missbrukspotential än tidigare antaget. Forskare vid Linköpings universitet kartlade 20 substanser genom in vitro-testning av dopamin-, noradrenalin- och serotoninöverförare för att förutsäga farlighetsprofiler innan de cirkulerar kliniskt. N-pyrrolidinkatinoner med metylendioxy-grupper—MDPiHP, MDPEP och MDPV—visade högst dopamin-potens, medan 3F-α-PHP och 4F-α-PiHP uppvisade högst dopaminselectivitet och därmed högsta missbrukspotential. Klorometan- och metilmetkatinoner följde ett amfetaminliknande mönster med balanserad dopamin- och noradrenalinverkan. Studien finansierades av svenska myndigheter och involverade Rättsmedicinalverket. För regionvård och läkemedelstillsynsmyndigheter utgör resultaten kritiska data för tidig upptäckt, klinisk beredskap och regleringsrekommendationer när nya substanser identifieras på marknaden.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: Employing in vitro human transporter inhibition assay and AequoScreen® 5-HT KEY RESULTS: 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-HT CONCLUSIONS AND IMPLICATIONS: 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.