Review Amphetamines, new psychoactive drugs and the monoamine transporter cycle 1,2 1 Harald H. Sitte and Michael Freissmuth 1 Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria 2 Center for Addiction Research and Science (AddRess), Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria In monoaminergic neurons, the vesicular transporters rule (Box 1). Hence, this large group of compounds is and the plasma membrane transporters operate in a relay. difficult to define on chemical grounds. An operational Amphetamine and its congeners target this relay to definition based on the pharmacology (‘amphetamine-like elicit their actions: most amphetamines are substrates, action’) falls short of accounting for the complex mode of which pervert the relay to elicit efflux of monoamines into action: in fact, there is a continuum ranging from amphet- the synaptic cleft. However, some amphetamines act as amine-triggered release to methylphenidate-induced transporter inhibitors. Both compound classes elicit pro- blockage of uptake. A clear-cut definition would facilitate found psychostimulant effects, which render them liable imposing legal restrictions on marketing activities. The to recreational abuse. Currently, a surge of new psycho- difficulties arising from a chemistry-based definition are active substances occurs on a global scale. Chemists also exemplified by cathinones: the naturally occurring bypass drug bans by ingenuous structural variations, cathinone is a ketone. It serves as a scaffold for numerous resulting in a rich pharmacology. A credible transport substitutions: methylation produces meth(yl)cathinone, model must account for their distinct mode of action which allows regulations restricting the sales of cathinone and link this to subtle differences in activity and unde- to be bypassed. However, cathinone derivatives are not sired, potentially deleterious effects. only used illicitly: they include the antidepressant drug bupropion and the anorectic agent diethylpropion. Syn- Amphetamines – a diverse class of compounds thetic analogs of methcathinone have recently become The amphetamines are a diverse class of chemical com- popular as ‘designer drugs’ or ‘legal highs’ on the illicit pounds. They comprise synthetic compounds and natu- drug market [4]. Often, they are referred to as ‘bath rally occurring alkaloids such as ephedrine and cathinone salts’, ‘plant food’, or ‘research chemicals’ to facilitate (Box 1), which are synthesized in the plant species Ephe- their distribution and to obviate prosecution. Popular dra and Catha, respectively. Extracts from these plants methcathinone derivatives are 4-methylmethcathinone have been used for their remedial and psychostimulant (mephedrone, Box 1) and 3,4-methylenedioxymethcathi- effects for millenia (for an excellent historical overview none (methylone). More recently, 3,4-methylenedioxypyr- see [1]). Laza˘r Edeleanu synthesized the eponymous com- rovalerone (MDPV, Box 1) has reached the market; it is pound amphetamine in Berlin in 1887 (Box 1); many an example of a very potent, psychoactive synthetic cath- derivatives were produced within the next two decades inone and illustrates the problem of a laissez-faire ap- [1]. The availability of pure compounds allowed their proach to recreational drug use: MDPV exerts stimulant- pharmacological characterization, which was initiated like effects at low doses, but life-threatening side effects by Sir Henry Dale [2]. Biel and Bopp [3] chemically are seen at high doses or upon chronic use [5]. Accordingly, defined an amphetamine as containing: (i) an unsubsti- the authorities have banned amphetamines including tuted phenyl ring, (ii) a two-carbon side chain between the the first-generation synthetic cathinones such as mephe- phenyl ring and nitrogen, (iii) an a-methyl group, and (iv) drone, methylone, and MDPV in the USA and the EU. a primary amino group (Box 1). Many compounds meet Ignorance is blatant with respect to new psychoactive these criteria. In addition, the targets (i.e., the mono- substances (NPS) which flood the drug market at present amine transporters) apparently interpret the rules in a (Box 2). Chemical substitutions may render a given drug flexible manner: for instance, methamphetamine, ephed- compatible with current legislation, but they may also rine, and methylphenidate violate the primary-amine introduce dramatic changes in the activity of the com- pound and in its mode of action. Widespread consumption Corresponding author: Sitte, H.H. ([email protected]). Keywords: psychostimulant; amphetamine; reverse transport; regulation; monoa- of NPS may be associated with health risks such as mine transporter; addiction. neurodegeneration. These are linked – at least in part 0165-6147/ – to the mode of action. Accordingly, it is of relevance to ß 2014 The Authors. Published by Elsevier Ltd. This is an open access article under elucidate the different modes of action of amphetamine, the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). http://dx.doi.org/10.1016/j.tips.2014.11.006 its congeners, and in particular of stimulant NPS. The Trends in Pharmacological Sciences, January 2015, Vol. 36, No. 1 41 Review Trends in Pharmacological Sciences January 2015, Vol. 36, No. 1 Box 1. Structural differences between amphetamines The chemical definition by Biel and Bopp [3] posits the presence of receptors [75]. Moreover, the individual structural differences (i) an unsubstituted phenyl ring, (ii) a two-carbon side chain between between the different amphetamines highlight the specificity the phenyl ring and a nitrogen, (iii) an a-methyl group, and (iv) a between monoamine transporters, for example the SERT over DAT primary amino group in a compound to qualify as an amphetamine selectivity of pCA and fenfluramine [1,76], or the DAT-preference of (Figure I). Panel (A) illustrates this rule. Panel (B) shows the trace D-amphetamine [75]. However, amphetamines also bind to non- amine phenethylamine which is produced in higher organisms, monoamine transporter targets such as adrenergic receptors [1] or while panels (C,D) show the structures of the plant alkaloids trace amine receptors [77]. These receptors form complexes with ephedrine and cathinone. Panels (E–I) show the structural diversity transporters [78]; trace amine-associated receptor (TAR) agonists in amphetamines, which either conform to (E) or violate the chemical (including amphetamines) inhibit uptake [79,80]. These observations definition of Biel and Bopp rule (F–I). Accordingly, amphetamines point to a possible role of TARs in the treatment of amphetamine are a diverse group of compounds that target the transporters for addiction. The compound structures are reproduced from the monoamine neurotransmitters, but do not engage their cognate PubChem database. (a) (b) (c) (4) H H H H N N H N H (2) C C O (1) (3) Basic chemistry Phenethylamine Ephedrine (d) H H (e) H H (f) N N H N O Cathinone D-amphetamine Methamphetamine (g) (h) (i) H N O O N O N HH H O O O 3,4-Methylene- Methylphenidate Mephedrone dioxypyrovalerone TRENDS in Pharmacological Sciences Figure I. Chemical structures of amphetamines. main targets of amphetamines (and presumably of many amphetamine has been studied for more than 100 years stimulant NPS) are the neurotransmitter:sodium sym- [2]. Nevertheless, there are still many open questions: (i) porters (NSS) for the monoamines dopamine (DAT/solute how do these compounds differ from physiological sub- carrier protein SLC6A3), serotonin (SERT/SLC6A4), and strates to act as efficient releasers? (ii) What is the role of noradrenaline/norepinephrine (NET/SLC6A2). Ampheta- protein kinases in triggering efflux? (iii) Does the oligo- mines are exogenous substrates of and generate a meric arrangement of monoamine transporters affect current through these transporters [6]. The action of the action of amphetamine? (iv) Why does amphetamine 42 Review Trends in Pharmacological Sciences January 2015, Vol. 36, No. 1 Box 2. New psychoactive substances: scrutinizing their mode of action The term ‘new psychoactive substances’ (NPS) refers to a wide variety initiate transporter-mediated monoamine efflux (i.e., reverse transport of compounds which elicit psychotomimetic effects. These drugs or release), whereas blockers do not. Importantly, amphetamine- include stimulants that are congeners of amphetamine or synthetic associated depolarization puts neurons at risk: in fact, the use of cathinones. Their street market names ‘designer drugs’, ‘bath salts’, fenfluramines has been associated not only with neuronal depletion of ‘plant food’, or ‘research chemicals’ imply an innocuous recreational 5-HT [76], but also with pulmonary hypertension and valvular heart consumption. However, NPS is not restricted to compounds that act like disease [83]. The latter arises from the long-term effect of serotonin on amphetamine: also cannabimimetics, sedative-hypnotics, and also the pulmonary vasculature. hallucinogens such as 2-CB (2,5-dimethoxy-4-bromophenethylamine), Two simple diagnostic assays can be employed to assess the nature a partial agonist at 5HT2A-receptors, and related receptor ligands are of the compound under scrutiny: (i) electrophysiological recording of also classified as NPS [81]. NPS are not harmless: 4-methyl-N- transport-associated currents and/or (ii) examination of the initiation methylcathinone (mephedrone) and 3,4-methylenedioxypyrrovalerone of reverse