1. Introduction
The emergence of New Psychoactive Substances (NPS) in the illicit drug market, including synthetic cathinones, continues to be a matter of public health concern. Their consumption is associated with several deaths and acute intoxications. As of 2018, 119 countries and territories have reported 890 NPS to the United Nations Office on Drugs and Crime, with more than 300 identified in the United States of America (USA). Although some of them are under law restrictions, others are easily available through online shops or through the darknet(United Nations Office on Drugs and Crime (UNODC); European Monitoring Centre for Drugs and Drug, 2019). When one of these NPS falls under legislative control, the drug market responds by producing different structurally related alternatives, through minor chemical modifications. For instance, when “first-generation cathinones” (i.e., methylone, mephedrone and 3,4-methylenedioxypyrovalerone (MDPV)) were classified by the Drug Enforcement Administration (DEA) as Schedule I compounds (Drug Enforcement Administration, Department of Justice, 2011), a “second-generation” emerged, which includes α-pyrrolidinovalerophenone (α-PVP) and pentedrone (Drug Enforcement Administration, Department of Justice, 2014). The simple removal of the 3,4-methylendioxy group from MDPV led to the α-PVP structure, which at that time was not scheduled, and largely replaced MDPV on the drug market. However, since the scientific evidence regarding their mode of action, toxicity and/or abuse potential are still missing, many other synthetic cathinones have not yet been scheduled by the concerning authorities.
It has been demonstrated that α-PVP acts as a potent blocker of the dopamine (DA) transporters (DAT) (Meltzer et al., 2006; Marusich et al., 2014). Preclinical studies have also described α-PVP to produce long-lasting increases in locomotor activity, to induce conditioned place preference and to fully substitute for discriminative stimulus effects of both cocaine and methamphetamine (Marusich et al., 2014; Gatch et al., 2015b). Moreover, α-PVP has also been shown to facilitate intracranial self-stimulation and maintain self-administration in rats (Watterson et al., 2014; Huskinson et al., 2017). Pentedrone is another “second-generation” cathinone closely related to α-PVP, only differing in its amino-group substituent (see Figure 1A). Similar to α-PVP, pentedrone also blocks DAT and exhibits psychostimulant, rewarding and reinforcing properties (Simmler et al., 2014; Gatch et al., 2015a; Hwang et al., 2017; Javadi-Paydar et al., 2018). Numerous structure-activity relationship (SAR) studies on synthetic cathinones have shown to correlate molecular properties of different substituents with their pharmacological and toxicological profile (Kolanos et al., 2015; Eshleman et al., 2017; Niello et al., 2019; Walther et al., 2019) (for review see also (Glennon and Dukat, 2016; Baumann et al., 2018)). Saha and colleagues demonstrated how modifications at both, α-carbon alkyl chain and the N-group of methcathinone, generate a “hybrid compound” that behaves as a blocker at DAT and as a releaser at the serotonin transporter (SERT) (Saha et al., 2015, 2019).
In this study, we explore different structural modifications in the amino-terminal group of synthetic cathinones by describing a set of five α-aminovalerophenone derivatives: pentedrone, α-ethylaminovalerophenone (N-ethyl-pentedrone), α-diethylaminovalerophenone (N,N-diethyl-pentedrone), α-PVP and α-piperidinevalerophenone (α-PpVP) (See Figure 1). This may shine light on how these structural modifications may shape their activity at monoamine transporters together with their psychostimulant and rewarding effects. Importantly, the present work also highlights pharmacological and behavioural effects of N-ethyl-pentedrone, a novel NPS currently available (www.erowid.com) and identified in fatal cases and seizures (Majchrzak et al., 2018; Zaami et al., 2018) with no legal ramifications to prevent its distribution for consumption . Moreover, we provide insights into other novel synthetic cathinones, which may appear as next generation NPS in the near future.
Accordingly, the aims of the present study were i) to characterize thein vitro pharmacology of five α-aminovalerophenone derivatives; ii) to study the interaction mechanism of these compounds at the molecular level by means of molecular docking; iii) to assess their potential psychostimulant and rewarding effects at different doses; iv) to establish a structure-activity relationship (SAR) between the different amino-substituents and their pharmacological profile. These were achieved by monoamine uptake and binding experiments, together with molecular docking to investigate the molecular aspects of α-aminovalerophenone derivatives. Combined with behavioural experiments in mice, which provided insight regarding their potential psychostimulant and rewarding effects, our study allowed to establish the SAR between the different amino-substituents and their pharmacological profile. Altogether, this study aims to provide a molecular and behavioural explanation for abuse liability associated with synthetic cathinones.