Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2AReceptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter

Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied, under medical guidance, as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using HEK cells stably expressing 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors (5-HT_1AR, 5-HT_2AR, 5HT_2CR respectively) or the serotonin transporter (SERT), we measured affinities, potencies and efficacies of 21 substituted tryptamines. With the exception of two 4-acetoxy compounds, substituted tryptamines exhibited affinities and potencies less than one micromolar at the 5-HT_2AR, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT_2CR, 5-HT_1AR, and SERT. Sorting by the ratio of 5-HT_2A to 5-HT_2C, 5-HT_1A, or SERT affinity revealed chemical determinants of selectivity. We found that while 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HT_2ARs versus 5-HT_1ARs and 5-HT_2CRs. 5-substituted compounds exhibited high affinities for 5-HT_1ARs, low affinities for 5-HT_2C­Rs, and a range of affinities for 5-HT_2ARs, resulting in selectivity for 5-HT_2ARs versus 5-HT_2CRs but not versus 5-HT_1ARs. Additionally, a number of psychedelics bound to SERT, with non-ring substituted tryptamines most consistently exhibiting binding. Interestingly, substituted tryptamines and known psychedelic standards exhibited a broad range of efficacies, which were lower as a class at 5-HT_2ARs compared to 5-HT_2CRs and 5-HT_1ARs. Conversely, coupling efficiency/amplification ratio was highest at 5-HT_2ARs in comparison to 5-HT_2CRs and 5-HT_1ARs. Significance Statement Synthetic substituted tryptamines represent both potential public health threats and potential treatments of psychiatric disorders. The substituted tryptamines tested differed in affinities, potencies and efficacies at 5-HT_2A, 5-HT_2C and 5HT_1A receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT_2A versus 5-HT_1A and 5-HT_2C receptors, and some bound SERT. This basic pharmacology of substituted tryptamines aids our understanding of the pharmacologic basis for their potential for harm and as therapeutic agents.