Concentration-response curves of substituted tryptamines in radioligand binding assays at 5-HT_2AR (A), 5-HT_2CR (B), 5-HT_1AR (C), and SERT (D). Data shown for substituted tryptamines are the means ± S.E.M. of three experiments (5-HT_1AR) or three to five experiments (5-HT_2AR, 5-HT_2CR, and SERT) conducted in duplicate.

Agonist activity of substituted tryptamines at recombinant 5-HT_2AR (A), 5-HT_2CR (B)_, 5-HT_1AR (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-HT_2AR IP-1 assay. n = 3–4 independent experiments. (B) 5-HT_2CR IP-1 assay. n = 3–5 independent experiments. (C) 5-HT_1AR [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.

Substituted tryptamines sorted by pK_i and pEC₅₀ for 5-HT_2AR (A), 5-HT_2CR (B), and 5-HT_1AR (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-HT_2ARs 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-HT_2CRs (middle panel). (C) 5-MeO- and N,N-substituted tryptamines exhibit highest affinities and potencies for 5-HT_1ARs (right panel).

Substituted tryptamines sorted by pK_i and pIC₅₀ at SERT to show relative affinity and potency. (A) Substituted tryptamines were sorted by pK_i of [¹²⁵I]RTI-55 binding or (B) sorted by pIC₅₀ of [³H]5-HT uptake at SERT. pK_i 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 K_i 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 K_i 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.

Substituted tryptamine receptor selectivity. Areas enclosed in red rectangles highlight compounds with low selectivity for 5-HT_2AR or that prefer 5-HT_1AR or 5-HT_2CR. 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-HT_2AR vs. 5-HT_2CR but limited selectivity for 5-HT_2AR or 5-HT_2CR vs. 5-HT_1AR or even preferentially bind 5-HT_1A receptors. (D) Substituted tryptamines were sorted by 5-HT_2AR binding affinity/³H]5-HT SERT uptake IC₅₀ or (E) 5-HT_2AR binding affinity/K_i 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-HT_2AR receptors over SERT. The two 4-MeO compounds in particular strongly preferred SERT over 5-HT_2AR receptors.

Integrating patterns of selectivity of substituted tryptamines. A number of tryptamines that are selective for 5-HT_2AR receptors are also either nonselective for 5-HT_2AR vs. SERT or prefer SERT (see compounds marked with warmer colors to indicate those that do not prefer 5-HT_2AR vs. SERT). The N,N-substituted tryptamines that were tested (DMT, DET, and DPT) are all relatively nonselective for 5-HT_2AR vs. SERT. There are several compounds, typically 4-substituted, that exhibit selectivity for 5-HT_2AR vs. 5-HT_1A and 5-HT_2CR and vs. SERT. The 5-MeO compounds tested prefer 5-HT_2AR relative to SERT.

Receptor efficacy. With the exception of most of the 4-AcO compounds, most tryptamines tested are full or near full agonists at 5-HT_1AR. All tryptamines tested were full agonists at 5-HT_2CR. Many of the tryptamines tested were partial agonists at 5-HT_2AR, 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.