Pharmacological profile of novel psychoactive benzofurans

Benzofurans, a class of newly used psychoactive substances, inhibit norepinephrine and serotonin uptake more than dopamine uptake, similar to MDMA and unlike methamphetamine. They also release monoamines and interact with trace amine-associated receptor 1, like classic amphetamines. Most benzofurans are partial 5-HT2A receptor agonists, similar to MDMA, but also activate 5-HT2B receptors, which is associated with heart valve fibrosis, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY potently interacts with 5-HT2 receptors and binds to TA1 receptors, indicating predominant hallucinogenic properties and a risk for vasoconstriction.

Study at a glance

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 2 C ‐ 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‐ HT 2A and 5‐ HT 2B 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 ( TA 1 receptor), similar to classic amphetamines. Most benzofurans were partial 5‐ HT 2A receptor agonists similar to MDMA , but also 5‐ HT 2B receptor agonists, unlike MDMA and methamphetamine. The benzodifuran 2 C ‐ B ‐ FLY very potently interacted with 5‐ HT 2 receptors and also bound to TA 1 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‐ HT 2B receptor activation associated with heart valve fibrosis. The pharmacology of 2 C ‐ B ‐ FLY indicates predominant hallucinogenic properties and a risk for vasoconstriction.