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Investigation of the structure-activity relationships of psilocybin analogues

Klein, AK, Chatha, M, Laskowski, LJ, Anderson, EI, Brandt, SD, Chapman, SJ, McCorvy, JD and Halberstadt, AL (2020) Investigation of the structure-activity relationships of psilocybin analogues. ACS Pharmacology & Translational Science. ISSN 2575-9108

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The 5-HT2A receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure-activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, SAR studies were conducted with 16 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT2 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT2A activation in vivo. All of the compounds acted as full or partial agonists at 5-HT2 subtypes, displaying similar potencies at 5-HT2A and 5-HT2B receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT2C receptors and higher 5-HT2B receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT2A potency of 4-hydroxy-N,N-dialkyltryptamines by about 10-20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as pro-drugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.

Item Type: Article
Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology & Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsptsci.0c00176
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: ACS Publications
Date Deposited: 24 Nov 2020 10:47
Last Modified: 14 Dec 2021 00:50
DOI or ID number: 10.1021/acsptsci.0c00176
URI: https://researchonline.ljmu.ac.uk/id/eprint/14072
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