(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology – March 01, 2022
Source: PubMed
Summary
Unexpectedly, a novel compound class, APBTs, influences brain chemistry without causing stimulant effects. Researchers investigated these sulfur-based analogs, finding they inhibit monoamine reuptake and release neurotransmitters, similar to MDMA. Despite this, they didn't induce hyperactivity in mice. Instead, these compounds activated serotonin receptors, producing psychedelic-like effects, evident by specific behavioral responses. This distinct profile, with strong psychedelic activity and minimal stimulation, suggests potential for therapeutic applications, such as in drug-assisted psychotherapy.
Abstract
Derivatives of (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) are new psychoactive substances which produce stimulant effects in vivo. (2-Aminopropyl)benzo[β]thiophene (APBT) is a novel sulfur-based analog of API and APB that has not been pharmacologically characterized. In the current study, we assessed the pharmacological effects of six APBT positional isomers in vitro, and three of these isomers (3-APBT, 5-APBT, and 6-APBT) were subjected to further investigations in vivo. Uptake inhibition and efflux assays in human transporter-transfected HEK293 cells and in rat brain synaptosomes revealed that APBTs inhibit monoamine reuptake and induce transporter-mediated substrate release. Despite being nonselective transporter releasers like MDMA, the APBT compounds failed to produce locomotor stimulation in C57BL/6J mice. Interestingly, 3-APBT, 5-APBT, and 6-APBT were full agonists at 5-HT2 receptor subtypes as determined by calcium mobilization assays and induced the head-twitch response in C57BL/6J mice, suggesting psychedelic-like activity. Compared to their APB counterparts, ABPT compounds demonstrated that replacing the oxygen atom with sulfur results in enhanced releasing potency at the serotonin transporter and more potent and efficacious activity at 5-HT2 receptors, which fundamentally changed the in vitro and in vivo profile of APBT isomers in the present studies. Overall, our data suggest that APBT isomers may exhibit psychedelic and/or entactogenic effects in humans, with minimal psychomotor stimulation. Whether this unique pharmacological profile of APBT isomers translates into potential therapeutic potential, for instance as candidates for drug-assisted psychotherapy, warrants further investigation.