Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)_2AReceptor (5-HT_2AR), 5-HT_2CR, 5-HT_1AR, and Serotonin Transporter

Abstract

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 1A R, 5-HT 2A R, 5HT 2C R 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 2A R, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT 2C R, 5-HT 1A R, 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 2A Rs versus 5-HT 1A Rs and 5-HT 2C Rs. 5-substituted compounds exhibited high affinities for 5-HT 1A Rs, low affinities for 5-HT 2C Rs, and a range of affinities for 5-HT 2A Rs, resulting in selectivity for 5-HT 2A Rs versus 5-HT 2C Rs but not versus 5-HT 1A Rs.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 2A Rs compared to 5-HT 2C Rs and 5-HT 1A Rs. Conversely,

Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice

“…These data are generally consistent with other reports of agonist activities of these tryptamines at 5-HT 2 receptors in the G q -calcium mobilization assay . Agonist activity of 4-PrO-DMT has not previously been reported but is consistent with agonist actions of related compounds in this assay. , As predicted by the present primary binding screen and previously reported by others, , 4-HO-DiPT had weak (EC 50 ≈ 6,400 nM) potency and/or partial agonist efficacy (∼72%) at 5-HT 2C relative to 5-HT and the other psychedelic tryptamines tested.…”

“…The present binding results are consistent with known differences in agonist activities (i.e., potency and efficacy) at 5-HT 2 receptors and behavioral effects for many of the tested tryptamine analogues in mouse HTR studies . The present receptor binding data for 4-HO-DiPT also agree with the findings of others who showed weak serotonin 2C receptor (5-HT 2C ) agonist potency as well as binding affinity. ,, …”

“…The present studies are the first to report the comprehensive receptor binding and target profiles for a set of tryptamine psychedelic NPS being used as alternatives to psilocybin in recreational drug markets and being explored as potential new medications, including 4-PrO-DMT. − Partial receptor profiles for 4-HO-DALT, 4-AcO-DALT, 4-HO-DiPT, and 4-HO-MET have been reported previously. , Prior results generally agree with the receptor binding affinity data reported here, but there are a few discrepancies worth noting. 4-HO-DALT was previously shown to have affinity at SERT of ∼5 μM in contrast to the affinity of ∼700 nM shown here .…”

“…In addition to the present data showing agonist activities of several of the psychedelic tryptamines at 5-HT 2 receptors (Figure S1, Table S1), functional agonist potencies for G αq -calcium signaling at 5-HT 2 receptor subtypes as well as the potencies to induce HTR in mice, have been reported by another group for most of the tested compounds . Other studies have examined the binding affinities as well as the potencies and efficacies of a large set of tryptamine psychedelics at 5-HT 2A , 5-HT 2C , and 5-HT 1A receptors. , However, the functional activities for other signaling pathways linked to 5-HT 2A and at other 5-HT receptors and targets are still largely unknown. This study fills an important gap in knowledge by providing a comprehensive evaluation of the potential non-5-HT 2A targets for psychedelic tryptamines, and complements the existing data regarding functional activities for compounds at 5-HT 2 receptors .…”

“…Inhibition constants for 5-HT receptors assessed are shown in Table , while inhibition constants for the most common non-5-HT receptor targets are listed in Table and Table . Many of the compounds displayed affinity for all 5-HT receptors assessed, similar to the findings for psilocin and psilacetin. − In general, the receptor binding results show that 4-hydroxy compounds have higher affinity across all 5-HT receptor targets when compared to 4-acetoxy analogues with the same N -alkyl groups. We previously demonstrated that 4-hydroxy and 4-acetoxy analogues of psilocybin display higher affinity for more 5-HT receptor subtypes when compared to their 4-phosphoryloxy counterparts .…”