Synthesis, Structural Characterization, and Pharmacological Activity of Novel Quaternary Salts of 4-Substituted Tryptamines.

Aeruginascin (4-phosphoryloxy-,,-trimethyltryptammonium) is an analogue of psilocybin (4-phosphoryloxy-,-dimethyltryptamine) that has been identified in several species of psilocybin-containing mushrooms. Our team previously reported the synthesis, structural characterization, and biological activity of the putative metabolite of aeruginascin (4-hydroxy-,,-trimethyltryptammonium; 4-HO-TMT) and its potential prodrug (4-acetoxy-,,-trimethyltryptammonium; 4-AcO-TMT). Here, we report the synthesis, structural characterization, and pharmacological activity of several quaternary tryptammonium analogues of 4-HO-TMT and 4-AcO-TMT, namely, 4-hydroxy-,-dimethyl--ethyltryptammonium (4-HO-DMET), 4-hydroxy-,-dimethyl---propyltryptammonium (4-HO-DMPT), and 4-hydroxy-,-dimethyl--isopropyltryptammonium (4-HO-DMiPT), as well as their hypothesized prodrugs 4-acetoxy-,-dimethyl--ethyltryptammonium (4-AcO-DMET), 4-acetoxy-,-dimethyl---propyltryptammonium (4-AcO-DMPT), and 4-acetoxy-,-dimethyl--isopropyltryptammonium (4-AcO-DMiPT). Compounds were synthesized using established methods, and structures were characterized by single-crystal X-ray diffraction. Test compounds were screened for in vitro pharmacological activity at a variety of receptors and transporters to determine potential targets of action. None of the compounds exhibited measurable affinity for the serotonin 2A receptor (5-HT), but several analogues had low micromolar affinity ( ) for the serotonin 1D receptor (5-HT) and serotonin 2B receptor (5-HT), where they appeared to be weak partial agonists with low micromolar potencies. Importantly, 4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM). The same 4-hydroxy analogues had low to sub-micromolar potencies (IC) for inhibition of 5-HT uptake at SERT in transfected cells (3.3-12.3 μM) and rat brain tissue (0.31-3.5 μM). Overall, our results show that quaternary tryptammonium analogues do not target 5-HT sites, suggesting the compounds lack psychedelic-like subjective effects. However, certain 4-hydroxy quaternary tryptammonium analogues may provide novel templates for exploring structure-activity relationships for selective actions at SERT.