ACS Publications. Most Trusted. Most Cited. Most Read
Synthesis and Structure–Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2024, 67, 8, 6144-6188
    Article

    Synthesis and Structure–Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist
    Click to copy article linkArticle link copied!

    • Geoffrey B. Varty*
      Geoffrey B. Varty
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      *Phone: (+1)908-500-8007. E-mail: [email protected]
      More by Geoffrey B. Varty
      Orcidhttps://orcid.org/0000-0002-7974-7566
    • Clinton E. Canal
      Clinton E. Canal
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States
      More by Clinton E. Canal
      Orcidhttps://orcid.org/0000-0002-7940-933X
    • Tina A. Mueller
      Tina A. Mueller
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      BioIVT, Hicksville, New York 11803, United States
      More by Tina A. Mueller
    • Joshua A. Hartsel
      Joshua A. Hartsel
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      Consultant, UPS PO Box #105-650, 25422 Trabuco Road, Lake Forest, California 92630, United States
      More by Joshua A. Hartsel
    • Richa Tyagi
      Richa Tyagi
      College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States
      More by Richa Tyagi
      Orcidhttps://orcid.org/0009-0001-9228-6311
    • Ken Avery
      Ken Avery
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Ken Avery
    • Michael E. Morgan
      Michael E. Morgan
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Michael E. Morgan
    • Amy C. Reichelt
      Amy C. Reichelt
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      Faculty of Biomedicine, University of Adelaide, Adelaide, South Australia 5005, Australia
      More by Amy C. Reichelt
    • Pradip Pathare
      Pradip Pathare
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Pradip Pathare
    • Erik Stang
      Erik Stang
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Erik Stang
    • Michael G. Palfreyman
      Michael G. Palfreyman
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Michael G. Palfreyman
    • Alex Nivorozhkin
      Alex Nivorozhkin
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
      More by Alex Nivorozhkin
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 8, 6144–6188
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.3c01961
    Published April 9, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

    Abstract

    Click to copy section linkSection link copied!
    Abstract Image

    Structure–activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1–3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

    Copyright © 2024 American Chemical Society

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. Add or change your institution or let them know you’d like them to include access.

    Supporting Information

    Click to copy section linkSection link copied!

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01961.

    • Molecular formula strings (CSV)

    • HTR and LMA for select phenethylamines; 5-HT2A receptor potency and in vitro metabolism of substituted phenylalkylamines and their deuterated analogs; HPLC method, LC–MS, NMR, TGA, DSC, and XRPD for CYB210010; off-target radioligand binding by the 5-HT receptor agonists, DOI and CYB210010; pharmacokinetics of CYB210010 in mouse plasma and brain after oral and subcutaneous administration; free fraction of CYB210010 in mouse and rat brain homogenates; NMR spectra, HPLC traces, and LC–MS for 38 compounds (PDF)

    Terms & Conditions

    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!
    Citation Statements
    Explore this article's citation statements on scite.ai
    powered by  Scite

    This article is cited by 2 publications.

    1. Mary O. Vu, B. Michael Butters, Clinton E. Canal, Xavier A. Figueroa. Defined radio wave frequencies attenuate the head-twitch response in mice elicited by (±)-2,5-dimethoxy-4-iodoamphetamine. Electromagnetic Biology and Medicine 2024, 43 (4) , 328-336. https://doi.org/10.1080/15368378.2024.2418552
    2. . Discovery of a Potent and Long-Acting Seretonin 5-HT2 Receptor Agonist. Synfacts 2024, 0761. https://doi.org/10.1055/s-0043-1763968
    Download PDF
    Go to Journal of Medicinal Chemistry
    Get e-Alerts
    Get e-Alerts

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 8, 6144–6188
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.3c01961
    Published April 9, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

    Article Views

    2515

    Altmetric

    -

    Citations

    2
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.