Investigation of the Structure-Activity Relationships of Psilocybin Analogues.

The 5-HT receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-,-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-,-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-,-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 ,-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 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT activation . All of the compounds acted as full or partial agonists at 5-HT subtypes, displaying similar potencies at 5-HT and 5-HT receptors, but some tryptamines with bulkier -alkyl groups had lower potency at 5-HT receptors and higher 5-HT receptor efficacy. In addition, -acetylation reduced the 5-HT potency of 4-hydroxy-,-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 -acetylated tryptamines may be deacetylated , acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.