Investigation of the Structure−Activity Relationships of Psilocybin Analogues

This animal study investigated the pharmacology and behavioral effects of psilocybin-analogs, with a substituted hydroxy or acetoxy group at the 4-position, and found they all consistently elicited psychedelic-like effects via the 5-HT2A receptor.


Introduction: 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, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,Ndialkyl substituents and either a 4-hydroxy or 4-acetoxy group.

Methods: 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.

Results: 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- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSDlike 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 prodrugs.

Discussion: In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.”

Authors: Adam K. Klein, Muhammad Chatha, Lauren J. Laskowski, Emilie I. Anderson, Simon D. Brandt, Stephen J. Chapman, John D. McCorvy & Adam L. Halberstadt

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