The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

Abstract

RationaleThe non-medical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called "benzofury" compounds, 5-(2aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models. Methods Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their Nmethyl derivatives 5-MAPB and 6-MAPB, in comparison to 3,4methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison to MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats. Results All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least 3-fold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection. Conclusions Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability, and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Pharmacotherapy of Patients Taking New Psychoactive Substances: A Systematic Review and Analysis of Case Reports

“…These types of NPS are potent inhibitors of norepinephrine, dopamine and serotonin reuptake. Animal studies have shown that 5-APB and 6-APB are potent agonists of 5-HT2B receptors (105,106). However, the frequency of use of this NPS group is very low.…”

Finding unknown stimulants applied in food supplements using Artificial Intelligence

“…Because of the interaction with 5-HT2B receptors, 6-APB is cardiotoxic with long-term use, but also has the potential for acute toxicity. It is a controlled substance in several countries, but remains one of the most sold new psychoactive substances in Europe (Brandt, et al, 2020;Chan, et al, 2013;Roque Bravo, et al, 2020).…”

“…It is only controlled in a few countries. (Brandt, et al, 2020;Roque Bravo, et al, 2020;Welter, et al, 2015).…”

Synthesis of 2-(5-(2-Aminopropyl)-2-hydroxyphenyl)acetic Acid, a Metabolite of the Drug 5-APB

“…In vitro studies in primary rat hepatocytes of the two benzofurans, 6-APB and 5-APB, showed that 5-APB Molbank 2023, 2023, M1629 2 of 7 displayed higher hepatotoxicity in these cellular models than its 6-isomer [12]. Some animal studies have revealed several metabolites in rat urine samples, which allowed the metabolism of 5-and 6-APB to be compared [13]. Generally, the phase I metabolism of these drugs involved (i) ring hydroxylation; (ii) ring cleavage; (iii) aldehyde reduction; (iv) aldehyde oxidation.…”

“…In vitro studies in primary rat hepatocytes of the two benzofurans, 6-APB and 5-APB, showed that 5-APB displayed higher hepatotoxicity in these cellular models than its 6-isomer [12]. Some animal studies have revealed several metabolites in rat urine samples, which allowed the metabolism of 5-and 6-APB to be compared [13].…”