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.