The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative
Karolina E. Kolaczynska, Jan Thomann, Marius C. Hoener, Matthias E. Liechti
International Journal of Molecular Sciences July 31, 2021 DOI: 10.3390/ijms22158277 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | HEK293 cells overexpressing human norepinephrine, dopamine, or serotonin transporters |
| Intervention | NEH |
| Topics | Serotonin |
| Keywords | Cathinone Pharmacology Potency Dopamine transporter Monoamine neurotransmitter Ic50 Serotonin transporter Receptor |
| Citations | 35 |
| Key points | All tested pyrovalerone cathinones are potent dopamine and norepinephrine transporter inhibitors with no serotonin transporter activity at concentrations below 10 µM, and 4F-PBP and NEH show high selectivity for the dopamine transporter, indicating strong psychostimulant effects and high abuse liability. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 5
- Synthetic cathinones in drug-facilitated sexual assault: A case report involving the novel generation substituted cathinone N-ethylpentedrone and a review of the literature. Forensic Science International June 1, 2024
- 4-Isobutylmethcathinone—A Novel Synthetic Cathinone with High In Vitro Cytotoxicity and Strong Receptor Binding Preference of Enantiomers Pharmaceuticals November 30, 2022
- Molecular Insights on New Psychoactive Substances (NPSs) International Journal of Molecular Sciences March 18, 2022
- Comprehensive in vitro profiling of traditional and emerging stimulants at monoamine transporters and the 5-HT2A receptor. British Journal of Pharmacology July 14, 2026
- Uncovering Structure-Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments. ACS Chemical Neuroscience February 21, 2024
Cites 19
- Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin Synapse 2000
- MDMA enhances emotional empathy and prosocial behavior Social Cognitive and Affective Neuroscience October 4, 2013
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects Neuropsychopharmacology November 16, 2019
- Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects Neuropsychopharmacology October 15, 2020
and 14 more in the library