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Research ArticleNeuropharmacology

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

Laura B. Kozell, Amy J. Eshleman, Tracy L. Swanson, Shelley H. Bloom, Katherine M. Wolfrum, Jennifer L. Schmachtenberg, Randall J. Olson, Aaron Janowsky and Atheir I. Abbas
Journal of Pharmacology and Experimental Therapeutics April 2023, 385 (1) 62-75; DOI: https://doi.org/10.1124/jpet.122.001454
Laura B. Kozell
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Amy J. Eshleman
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Tracy L. Swanson
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Shelley H. Bloom
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Katherine M. Wolfrum
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Jennifer L. Schmachtenberg
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Randall J. Olson
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Aaron Janowsky
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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Atheir I. Abbas
Veterans Affairs Portland Health Care System (L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and Departments of Psychiatry (L.B.K., A.J.E., T.L.S., A.J., A.I.A.) and Behavioral Neuroscience (L.B.K., R.J.O., A.I.A.), Oregon Health & Science University, Portland, Oregon
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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.

Footnotes

    • Received September 22, 2022.
    • Accepted January 10, 2023.
  • Author and/or study funding was provided by the US Department of Justice Drug Enforcement Administration [Grant D-22-OD-0001] (to L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.), Department of Veterans Affairs Career Scientist Program [Grant 14S-RCS-006] (to A.J.), National Institutes of Health National Institute on Drug Abuse Interagency Agreement [Grant ADA12013] (to L.B.K., A.J.E., T.L.S., S.H.B., K.M.W., J.L.S., A.J., A.I.A.) and National Institute on Drug Abuse [Grant T32-DA007262-30] (to R.J.O.), the Oregon Health & Science University Physician-Scientist Award [Grant 60678300] (to A.I.A.), and the Portland Veterans Affairs Research Foundation [Grant 429999] (to A.I.A.). The contents do not represent the views of the US Department of Veterans Affairs, US Department of Justice, Drug Enforcement Administration, or US Government.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/jpet.122.001454.

  • U.S. Government work not protected by U.S. copyright.
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleNeuropharmacology

Substituted Tryptamine Activity at 5-HT Receptors and SERT

Laura B. Kozell, Amy J. Eshleman, Tracy L. Swanson, Shelley H. Bloom, Katherine M. Wolfrum, Jennifer L. Schmachtenberg, Randall J. Olson, Aaron Janowsky and Atheir I. Abbas
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 62-75; DOI: https://doi.org/10.1124/jpet.122.001454

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Research ArticleNeuropharmacology

Substituted Tryptamine Activity at 5-HT Receptors and SERT

Laura B. Kozell, Amy J. Eshleman, Tracy L. Swanson, Shelley H. Bloom, Katherine M. Wolfrum, Jennifer L. Schmachtenberg, Randall J. Olson, Aaron Janowsky and Atheir I. Abbas
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 62-75; DOI: https://doi.org/10.1124/jpet.122.001454
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