Pharmacological profile of novel psychoactive benzofurans.

BJP British Journal of Pharmacology RESEARCH PAPER Pharmacological profile of novel psychoactive benzofurans DOI:10.1111/bph.13128 www.brjpharmacol.org Correspondence Prof. Dr. Matthias E Liechti, Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Hebelstrasse 2, Basel, CH-4031, Switzerland. E-mail: ---------------------------------------------------------------- Received 23 December 2014 Revised Anna Rickli1, Simone Kopf1, Marius C Hoener2 and Matthias E Liechti1 6 February 2015 1 9 March 2015 Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department Accepted of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland, and Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, 2 Switzerland BACKGROUND AND PURPOSE Benzofurans are newly used psychoactive substances, but their pharmacology is unknown. The aim of the present study was to pharmacologically characterize benzofurans in vitro. EXPERIMENTAL APPROACH We assessed the effects of the benzofurans 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB and 5-MAPDB and benzodifuran 2C-B-FLY on the human noradrenaline (NA), dopamine and 5-HT uptake transporters using HEK 293 cells that express the respective transporters. We also investigated the release of NA, dopamine and 5-HT from monoamine-preloaded cells, monoamine receptor-binding affinity and 5-HT2A and 5-HT2B receptor activation. KEY RESULTS All of the benzofurans inhibited NA and 5-HT uptake more than dopamine uptake, similar to methylenedioxymethamphetamine (MDMA) and unlike methamphetamine. All of the benzofurans also released monoamines and interacted with trace amine-associated receptor 1 (TA1 receptor), similar to classic amphetamines. Most benzofurans were partial 5-HT2A receptor agonists similar to MDMA, but also 5-HT2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY very potently interacted with 5-HT2 receptors and also bound to TA1 receptors. CONCLUSIONS AND IMPLICATIONS Despite very similar structures, differences were found in the pharmacological profiles of different benzofurans and compared with their amphetamine analogues. Benzofurans acted as indirect monoamine agonists that interact with transporters similarly to MDMA. The benzofurans also interacted with 5-HT receptors. This pharmacological profile probably results in MDMA-like entactogenic psychoactive properties. However, benzofurans induce 5-HT2B receptor activation associated with heart valve fibrosis. The pharmacology of 2C-B-FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction. Abbreviations 2C-B-FLY, 8-bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine; 4-APB, 4-(2-aminopropyl)benzofuran; 5-APB, 5-(2-aminopropyl)benzofuran; 5-APDB, 5-(2-aminopropyl)-2,3-dihydrobenzofuran; 5-EAPB, 5-(2-ethylaminopropyl) benzofuran; 5-MAPDB, 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine; 6-APB, 6-(2-aminopropyl)benzofuran; 6-APDB, 6-(2-aminopropyl)-2,3-dihydrobenzofuran; 7-APB, 7-(2-aminopropyl)benzofuran; β-keto-MDA, β-keto-3,4methylenedioxyamphetamine; bromo-dragonFLY, 1-(8-bromobenzo[1,2-b;4,5-b′]difuran-4-yl)-2-aminopropane; DAT, dopamine transporter; MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; NET, noradrenaline transporter; SERT, 5-HT transporter; TA receptor, trace amine-associated receptor 3412 British Journal of Pharmacology (2015) 172 3412–3425 © 2015 The British Pharmacological Society Novel psychoactive benzofurans BJP Tables of Links TARGETS LIGANDS GPCRsa Transportersb 5-HT Noradrenaline Pyrilamine 5-HT1A receptor D1 receptor DAT Butaclamol Mazindole Rauwolscine 5-HT2A receptor D2 receptor NET Citalopram MDMA Risperidone 5-HT2B receptor D3 receptor SERT Clozapine Mesulergine RO5166017 5-HT2C receptor H1 receptor Dopamine Methamphetamine SCH23390 α1A adrenoceptor TA1 receptor Ketanserin Mianserin Spiperone LSD Phentolamine WIN35428 Nisoxetine Prazosin α2A adrenoceptor These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (a,bAlexander et al., 2013a,b). Introduction Novel psychoactive substances are newly used designer drugs (‘Internet drugs’, ‘research chemicals’, ‘legal highs’) that potentially pose similar health risks to classic illicit substances. In recent years, the number of newly detected psychoactive substances on the illicit drug market has dramatically increased. In the European Union, 41 novel psychoactive substances were identified for the first time in 2010, 49 were identified in 2011, 73 were identified in 2012 and 81 were identified in 2013 within the European Early Warning System (EMCDDA, 2014). Benzofurans are a group of novel psychoactive substances (King, 2014) of particular interest because they are structurally very similar to the popular recreational drug 3,4methylenedioxymethamphetamine (MDMA) and its active metabolite 3,4-methylenedioxyamphetamine (MDA; Greene, 2013). 5-(2-Aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran) (6-APB) are benzofuran analogues of MDA (Figure 1). 5-(2-Aminopropyl)-2,3dihydrobenzofuran (5-APDB) and 6-(2-aminopropyl)-2,3dihydrobenzofuran (6-APDB) are dihydrobenzofuran analogues (Figure 1) that were originally synthesized for research purposes (Monte et al., 1993). 4-(2- Figure 1 Chemical structures of benzofurans and related amphetamines. British Journal of Pharmacology (2015) 172 3412–3425 3413 BJP A Rickli et al. Aminopropyl)benzofuran (4-APB) and 7-(2aminopropyl)benzofuran (7-APB) are positional isomers of 5-APB and 6-APB. 1-(2,3-Dihydrobenzofuran-5-yl)-Nmethylpropan-2-amine (5-MAPDB) is a dihydrobenzofuran analogue of MDMA, and 5-(2-ethylaminopropyl)benzofuran (5-EAPB) is a benzofuran analogue of MDMA but with an N-ethyl group (Figure 1). 5-APB and 6-APB appeared on the drug market in 2010– 2011 (Chan et al., 2013; Jebadurai et al., 2013; Stanczuk et al., 2013; Archer et al., 2014; Elliott and Evans, 2014; King, 2014), with reports of intoxication (Chan et al., 2013; Greene, 2013; Jebadurai et al., 2013; Seetohul and Pounder, 2013). 4-APB was first reported to the EMCDDA in 2010 (King, 2014) and is typically detected in products that are sold as 6-APB as a by-product (Stanczuk et al., 2013; Strano Rossi et al., 2014). Users report that the effects of 5-APB and 6-APB are comparable with MDMA but more intense (Greene, 2013; Jebadurai et al., 2013). Adverse effects include nausea, sympathomimetic stimulation and agitation (Chan et al., 2013; Greene, 2013). 5-APDB and 6-APDB were first reported to the EMCDDA in 2012, and another three benzofurans, including 5-EAPB, were first repor (...truncated)