The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative
International Journal of Molecular Sciences – July 31, 2021
Source: OpenAlex
Summary
In Forensic Toxicology and Drug Analysis, certain Cathinone derivatives show extreme Potency, primarily targeting the Dopamine transporter. These pyrovalerone compounds, relevant in Psychedelics and Drug Studies, exhibit IC50 values as low as 0.02 μM for dopamine uptake inhibition, demonstrating significant Neurotransmitter Receptor Influence on Behavior. Chemistry reveals they largely ignore the Serotonin transporter, showing no Serotonin Transporter activity below 10 μM. For instance, 4F-PBP and NEH exhibit high selectivity for the Dopamine transporter (DAT/SERT ratio 264–356). This Pharmacology suggests strong psychostimulant effects from these Monoamine neurotransmitter inhibitors.
Abstract
Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02–8.7 μM) and NET inhibitors (IC50 = 0.03–4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17–0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264–356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.