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. 2023 Apr;385(1):62-75.
doi: 10.1124/jpet.122.001454. Epub 2023 Jan 20.

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

Laura B Kozell  1 , Amy J Eshleman  1 , Tracy L Swanson  1 , Shelley H Bloom  1 , Katherine M Wolfrum  1 , Jennifer L Schmachtenberg  1 , Randall J Olson  1 , Aaron Janowsky  1 , Atheir I Abbas  2
Affiliations

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

Laura B Kozell et al. J Pharmacol Exp Ther. 2023 Apr.

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 human embryonic kidney cells stably expressing 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT2C receptors (5-HT1AR, 5-HT2AR, and 5HT2CR, 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-HT2AR, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT2CR, 5-HT1AR, and SERT. Sorting by the ratio of 5-HT2A to 5-HT2C, 5-HT1A, 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-HT2ARs versus 5-HT1ARs and 5-HT2CRs. 5-substituted compounds exhibited high affinities for 5-HT1ARs, low affinities for 5-HT2CRs, and a range of affinities for 5-HT2ARs, resulting in selectivity for 5-HT2ARs versus 5-HT2CRs but not versus 5-HT1ARs. 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-HT2ARs compared with 5-HT2CRs and 5-HT1ARs. Conversely, coupling efficiency/amplification ratio was highest at 5-HT2ARs in comparison with 5-HT2CRs and 5-HT1ARs. 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)2A, 5-HT2C, and 5HT1A receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT2A versus 5-HT1A and 5-HT2C 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.

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Figures

Fig. 1.
Fig. 1.
Structures of tested substituted tryptamines and standards. The tryptamine backbone is highlighted in red. Structures of test compounds 5-HT, LSD, METH and DOM are shown. For each of the compounds tested the R1-R4 substitution is shown in the table on the right.
Fig. 2.
Fig. 2.
Concentration-response curves of substituted tryptamines in radioligand binding assays at 5-HT2AR (A), 5-HT2CR (B), 5-HT1AR (C), and SERT (D). Data shown for substituted tryptamines are the means ± S.E.M. of three experiments (5-HT1AR) or three to five experiments (5-HT2AR, 5-HT2CR, and SERT) conducted in duplicate.
Fig. 3.
Fig. 3.
Agonist activity of substituted tryptamines at recombinant 5-HT2AR (A), 5-HT2CR (B), 5-HT1AR (C), and inhibition of [3H]5-HT uptake at SERT (D). All receptor data, conducted in duplicate, were normalized to the maximal effect of 5-HT, which was measured on each experimental day. (A) 5-HT2AR IP-1 assay. n = 3–4 independent experiments. (B) 5-HT2CR IP-1 assay. n = 3–5 independent experiments. (C) 5-HT1AR [35S]GTPγS binding. n = 3 to 4 independent experiments. (D) Inhibition of [3H]5-HT uptake by SERT. n = 4 to 5 independent experiments conducted with duplicate determinations. Data shown are the means ± S.E.M.
Fig. 4.
Fig. 4.
Substituted tryptamines sorted by pKi and pEC50 for 5-HT2AR (A), 5-HT2CR (B), and 5-HT1AR (C) to show ordered relative affinities (top row) and relative potencies (bottom row) for all compounds to emphasize any chemical bases for affinity and potency. (A) Both 4- and 5-substituted tryptamines exhibit a broad range of affinities and potencies for 5-HT2ARs depending on the N,N substitutions (left panel). (B) 5-MeO and N,N DiPT –substituted tryptamines exhibit the lowest affinities and potencies for 5-HT2CRs (middle panel). (C) 5-MeO- and N,N-substituted tryptamines exhibit highest affinities and potencies for 5-HT1ARs (right panel).
Fig. 5.
Fig. 5.
Substituted tryptamines sorted by pKi and pIC50 at SERT to show relative affinity and potency. (A) Substituted tryptamines were sorted by pKi of [125I]RTI-55 binding or (B) sorted by pIC50 of [3H]5-HT uptake at SERT. pKi or pIC50 of the partner assay ([3H]5-HT uptake for (A) and [125I]RTI-55 binding for (B) were included alongside the sorted column. Of the tryptamines tested, 4-MeO-substituted tryptamines exhibit the highest binding at the RTI-55 and 5-HT uptake sites on SERT. Other 4-substituted N,N-diisopropyl and non–ring-substituted N,N-diethyl tryptamines predominantly exhibit binding to the [3H]5-HT site of SERT. C) Substituted tryptamines were sorted by the ratio of Ki vs. [125I]RTI-55 and IC50 vs. [3H]5-HT at SERT. Of the tryptamines tested, 4-AcO-substituted compounds and those with only N,N-substitutes exhibited the highest ratios of Ki at the [125I]RTI-55 binding site on SERT vs. IC50 competing against 3H]5-HT. Compounds with higher ratios are more substrate-like at SERT.
Fig. 6.
Fig. 6.
Substituted tryptamine receptor selectivity. Areas enclosed in red rectangles highlight compounds with low selectivity for 5-HT2AR or that prefer 5-HT1AR or 5-HT2CR. Substituted tryptamines were sorted by receptor-receptor selectivity ratio (A) 2A/1A ratios, (B) 2A/2C ratios, and (C) 2C/1A ratios. Of the tryptamines tested, 5-MeO-substituted compounds and those with only N,N-substitutions tend to exhibit moderate selectivity for 5-HT2AR vs. 5-HT2CR but limited selectivity for 5-HT2AR or 5-HT2CR vs. 5-HT1AR or even preferentially bind 5-HT1A receptors. (D) Substituted tryptamines were sorted by 5-HT2AR binding affinity/3H]5-HT SERT uptake IC50 or (E) 5-HT2AR binding affinity/Ki at SERT vs. [125I]RTI-55 binding. Of the tryptamines tested, DiPT-substituted compounds and those with only N,N-substitutions tended to exhibit decreased selectivity for 5-HT2AR receptors over SERT. The two 4-MeO compounds in particular strongly preferred SERT over 5-HT2AR receptors.
Fig. 7.
Fig. 7.
Integrating patterns of selectivity of substituted tryptamines. A number of tryptamines that are selective for 5-HT2AR receptors are also either nonselective for 5-HT2AR vs. SERT or prefer SERT (see compounds marked with warmer colors to indicate those that do not prefer 5-HT2AR vs. SERT). The N,N-substituted tryptamines that were tested (DMT, DET, and DPT) are all relatively nonselective for 5-HT2AR vs. SERT. There are several compounds, typically 4-substituted, that exhibit selectivity for 5-HT2AR vs. 5-HT1A and 5-HT2CR and vs. SERT. The 5-MeO compounds tested prefer 5-HT2AR relative to SERT.
Fig. 8.
Fig. 8.
Receptor efficacy. With the exception of most of the 4-AcO compounds, most tryptamines tested are full or near full agonists at 5-HT1AR. All tryptamines tested were full agonists at 5-HT2CR. Many of the tryptamines tested were partial agonists at 5-HT2AR, including a sizable number that were weak partial agonists with less than 50% efficacy. At the bottom of each heat map is the mean efficacy of the substituted tryptamines tested at each receptor.
Fig. 9.
Fig. 9.
Coupling efficiency of substituted tryptamines compared with 5-HT. To assess G-protein coupling efficiency, or amplification ratio, after binding of each chemical to receptor, we calculated a ratio of the Ki to EC50 relative to that ratio with 5-HT. Many but not all known psychedelics exhibit higher coupling efficiency than 5-HT at 5-HT2AR but lower coupling efficiency at 5-HT2CR. The mean amplification ratio was calculated as the average of individual amplification ratios. As a class, the compounds tested exhibit the highest average ratio at 5-HT2AR, higher than for 5-HT1AR and 5-HT2CR. At the bottom of each heat map is the mean amplification ratio of the substituted tryptamines tested at each receptor.
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