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(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice

Rudin, D, McCorvy, JD, Glatfelter, GC, Luethi, D, Szöllősi, D, Ljubišić, T, Kavanagh, PV, Dowling, G, Holy, M, Jaentsch, K, Walther, D, Brandt, SD, Stockner, T, Baumann, AL and Sitte, HH (2021) (2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice. Neuropsychopharmacology. ISSN 0893-133X

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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 non-selective 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.

Item Type: Article
Uncontrolled Keywords: 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
Subjects: Q Science > QP Physiology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Springer Nature
Date Deposited: 22 Oct 2021 10:11
Last Modified: 11 Nov 2021 12:30
DOI or Identification number: 10.1038/s41386-021-01221-0
URI: https://researchonline.ljmu.ac.uk/id/eprint/15682

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