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. 2015 Jul;172(13):3412-25.
doi: 10.1111/bph.13128. Epub 2015 Apr 24.

Pharmacological profile of novel psychoactive benzofurans

Anna Rickli  1 , Simone Kopf  1 , Marius C Hoener  2 , Matthias E Liechti  1
Affiliations

Pharmacological profile of novel psychoactive benzofurans

Anna Rickli et al. Br J Pharmacol. 2015 Jul.

Abstract

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.

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Figures

Figure 1
Figure 1
Chemical structures of benzofurans and related amphetamines.
Figure 2
Figure 2
Monoamine uptake transporter inhibition. Concentration–response curves show the uptake inhibition of [3H]-NA, [3H]-dopamine and [3H]-5-HT in HEK 293 cells transfected with the respective monoamine transporter. The data are expressed as the mean ± SEM of three to four independents experiments. Curves were fitted to the data with non-linear regression. The corresponding IC50 values are shown in Table 1.
Figure 3
Figure 3
Monoamine release. Monoamine release was induced by a high concentration of the compound (100 μM) after preloading the transporter-transfected cells with the respective radiolabelled monoamine. All of the benzofurans released NA, dopamine and 5-HT similarly to methamphetamine and MDMA. In contrast, the benzodifuran 2CB-FLY was not a monoamine releaser. Transporter blockers induced non-specific ‘pseudo-efflux’ (horizontal dashed line, open bars), which arises from substrate that diffuses out of the cells and from subsequent reuptake inhibition. Compounds that produced significantly more monoamine efflux (*P < 0.05, **P < 0.01, ***P < 0.001) compared with the respective non-releasing uptake inhibitors (negative controls, open bars) were considered monoamine releasers. The data are expressed as the mean ± SEM of three to four independent experiments.
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