Investigation of the Structure-Activity Relationships of Psilocybin Analogues.
Abstract
The 5-HT<sub>2A</sub> receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-<i>N</i>,<i>N</i>-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-<i>N</i>,<i>N</i>-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-<i>N</i>,<i>N</i>-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 <i>N</i>,<i>N</i>-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-HT<sub>2</sub> subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT<sub>2A</sub> activation <i>in vivo</i>. All of the compounds acted as full or partial agonists at 5-HT<sub>2</sub> subtypes, displaying similar potencies at 5-HT<sub>2A</sub> and 5-HT<sub>2B</sub> receptors, but some tryptamines with bulkier <i>N</i>-alkyl groups had lower potency at 5-HT<sub>2C</sub> receptors and higher 5-HT<sub>2B</sub> receptor efficacy. In addition, <i>O</i>-acetylation reduced the <i>in vitro</i> 5-HT<sub>2A</sub> potency of 4-hydroxy-<i>N</i>,<i>N</i>-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 LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that <i>O</i>-acetylated tryptamines may be deacetylated <i>in vivo</i>, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.
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