Serotonergic Polypharmacology of 2-Halogenated Tryptamines

Yacoub, J.; Bray, E.; Bayyat, J.; Glatfelter, G. C.; Leake, A.; Buitrago, E. M.; Maitland, A. D.; Partilla, J.; Cavalco, N. G.; Schalk, S. S.; Lammers, J. C.; Baumann, M. H.; McCorvy, J.; Leahy, J. W.; Gulick, D.; Witowski, C. G.; von Salm, J. L.

doi:10.64898/2026.04.16.718915

bioRxiv · 10.64898/2026.04.16.718915

Serotonergic Polypharmacology of 2-Halogenated Tryptamines

Yacoub, J.·Bray, E.·Bayyat, J.·Glatfelter, G. C.·Leake, A.·Buitrago, E. M.·Maitland, A. D.·Partilla, J.·Cavalco, N. G.·Schalk, S. S.·Lammers, J. C.·Baumann, M. H.·McCorvy, J.·Leahy, J. W.·Gulick, D.·Witowski, C. G.·von Salm, J. L.

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Abstract

Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized 2-halogenated derivatives of DMT and psilacetin to reduce 5-HT2A/5-HT2B activity while retaining engagement of therapeutically relevant targets, particularly 5-HT6, 5-HT2C, and 5-HT1B. This study demonstrated that 2-position halogenation decreased affinities, potencies, and efficacies at 5-HT2A and 5-HT1A receptors while preserving potent 5-HT6 agonism, especially for 2-Br-psilocin. The analogues exhibited reduced affinities at 5-HT2B and hERG ion channels, suggesting safer cardiac valve and cardiotoxic profiles. In C57BL/6J mice, 2-Br-psilacetin did not induce the head-twitch response and attenuated 2,5 dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch behavior, suggesting a reduced potential for inducing psychedelic effects. Behavioral assays further revealed improvements in stress-induced affective measures and hippocampus-independent cued learning at intermediate doses. These findings identify 2-halogenated tryptamines as polypharmacological serotonergic ligands with reduced psychoactivity and cardiac valve and toxic liabilities, supporting their potential as next-generation psychedelic-inspired therapeutics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/718915v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@17975a5org.highwire.dtl.DTLVardef@11ae1f1org.highwire.dtl.DTLVardef@1e7a00aorg.highwire.dtl.DTLVardef@1bbfcc8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yacoub, J., Bray, E., Bayyat, J., Glatfelter, G. C., Leake, A., Buitrago, E. M., Maitland, A. D., Partilla, J., Cavalco, N. G., Schalk, S. S., Lammers, J. C., Baumann, M. H., McCorvy, J., Leahy, J. W., Gulick, D., Witowski, C. G., von Salm, J. L.. 2026-04-21. Serotonergic Polypharmacology of 2-Halogenated Tryptamines. https://doi.org/10.64898/2026.04.16.718915

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