Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.
Abstract
Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT<sub>2</sub>) agonists. Specifically, we examine the 5-HT<sub>2</sub> pharmacology of the direct indazole analogs of 5-methoxy-<i>N</i>,<i>N</i>-dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT<sub>2</sub> subtype selectivity for these analogs, particularly for the 5-HT<sub>2B</sub> receptor subtype. Within this series, the potent analog VU6067416 (<b>19d</b>) was optimized to have suitable preclinical pharmacokinetic properties for <i>in vivo</i> dosing, although potent 5-HT<sub>2B</sub> agonist activity precluded further characterization for this series. Additionally, <i>in silico</i> docking studies suggest that the high potency of <b>19d</b> may be a consequence of a halogen-bonding interaction with Phe234<sup>5.38</sup> in the 5-HT<sub>2A</sub> orthosteric pocket.
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