Investigation of the Structure–Activity Relationships of Psilocybin Analogues

[Image: see text] The 5-HT(2A) 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,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-HT(2) subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT(2A) activation in vivo. All of the compounds acted as full or partial agonists at 5-HT(2) subtypes, displaying similar potencies at 5-HT(2A) and 5-HT(2B) receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT(2C) receptors and higher 5-HT(2B) receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT(2A) 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 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 prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.