Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT) Receptor (5-HTR), 5-HTR, 5-HTR, 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 human embryonic kidney cells stably expressing 5-hydroxytryptamine (5-HT), 5-HT, and 5-HT receptors (5-HTR, 5-HTR, and 5HTR, 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-HTR, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HTR, 5-HTR, and SERT. Sorting by the ratio of 5-HT to 5-HT, 5-HT, or SERT affinity revealed chemical determinants of selectivity. We found that although 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HTRs versus 5-HTRs and 5-HTRs. 5-substituted compounds exhibited high affinities for 5-HTRs, low affinities for 5-HTRs, and a range of affinities for 5-HTRs, resulting in selectivity for 5-HTRs versus 5-HTRs but not versus 5-HTRs. 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-HTRs compared with 5-HTRs and 5-HTRs. Conversely, coupling efficiency/amplification ratio was highest at 5-HTRs in comparison with 5-HTRs and 5-HTRs. 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-hydroxytryptamine (5-HT), 5-HT, and 5HT receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT versus 5-HT and 5-HT receptors, and some bound SERT. This basic pharmacology of substituted tryptamines helps us understand the pharmacologic basis of their potential for harm and as therapeutic agents.