Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Abstract

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transportermediated monoamine efflux with weak to no activity at pre-or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS.

Hazard Characterization of Synthetic Cathinones Using Viability, Monoamine Reuptake, and Neuronal Activity Assays

“…The process of obtaining cells in suspension can cause changes in cell morphology and damage to membrane proteins, resulting in cellular dysfunction and stress responses (Huang et al, 2010). This may increase the sensitivity of cells to the effect of toxicants, as was reported by Simmler and Liechti (2017), who stated that drugs were less potent releasers when attached cells were used compared to cells in suspension.…”

Cognitive deficits and neurotoxicity induced by synthetic cathinones: is there a role for neuroinflammation?

“…Synthetic cathinones vary widely in their structure-activity relationships with respect to DAT:SERT ratios, affinity for VMAT2, lipophilicity, and BBB permeability, as well as the biological activity of cathinone stereoisomers (Luethi et al 2018;Negus and Banks 2017;Simmler and Liechti 2017;Valente et al 2014). While some in vitro evidence has hinted at potential relationships between chemical structure (i.e., acyl chain length and presence of methyl groups) and cytotoxicity and abuse potential (Gaspar et al 2018), structure-activity relationships related to neurocognitive dysfunction, neuroinflammation and neurotoxicity…”

“…On the other hand, other cathinone derivatives such as mephedrone induce the release of monoamines and block reuptake, similar to the actions of MDMA and methamphetamine (Baumann et al 2012;Simmler et al 2013;Simmler et al 2014). Frequently, transporter affinities of various cathinones are expressed as a ratio of DAT:SERT, with higher values indicating a preferential affinity for DAT and possessing a higher potential for compulsive and abuse-like intake patterns, and lower DAT:SERT ratios indicate a preferential affinity for SERT and generally entactogenic and producing episodic intake patterns similar to those observed with MDMA (Negus and Banks 2017;Simmler and Liechti 2017;Simmons et al 2018). DAT-preferring synthetic cathinones induce depolarizing inward sodium currents at this transporter (Kolanos et al 2013), whereas MDMA-like synthetic cathinones induce inward currents but have a much slower rate of dissociation from the transporter, producing persistent leak currents (Dolan et al 2018).…”

“…The known pharmacological mechanisms of action of synthetic cathinones generally fall into one of two categories: blockade of presynaptic reuptake transporters for monoamines (dopamine, DA; norepinephrine, NE; serotonin, 5-HT), or action as a substrate for these transporters as well as the vesicular monoamine transporter 2 (VMAT2), the latter of which results in substantial efflux of monoamines from presynaptic terminals (Simmler and Liechti 2017;Simmons et al 2018). Cathinone itself was originally characterized as an amphetamine-like monoamine releasing agent (Kalix 1980;1981;1982) but additional studies have suggested it has DA reuptake inhibiting properties as well (Wagner et al 1982).…”

Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs

“…MDPV and related compounds containing a pyrrolidine ring are collectively known as pyrrolidinophenones. Like other stimulant drugs, bath salts cathinones exert their effects by binding to transporter proteins on the surface of nerve cells that synthesize the monoamine neurotransmitters dopamine, norepinephrine, and serotonin (5-HT) [23] [24, this volume]. In order to understand the precise mechanism of action for cathinone analogs at the molecular level, it is essential to first consider the physiological role of monoamine transporters and the types of drugs targeting these proteins.…”