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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 | Journal of Medicinal Chemistry
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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
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    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
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    • 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]
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      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
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    • 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
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    • Richa Tyagi
      Richa Tyagi
      College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States
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      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
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      Michael E. Morgan
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
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    • 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
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      Pradip Pathare
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
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      Erik Stang
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
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      Michael G. Palfreyman
      Cybin IRL Limited, North Wall Quay, 1 Spencer Dock, Dublin 1 DO1 X9R7, Ireland
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      Alex Nivorozhkin
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 8, 6144–6188
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    https://doi.org/10.1021/acs.jmedchem.3c01961
    Published April 9, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    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.

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    Supporting Information

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    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)

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    Cited By

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    This article is cited by 6 publications.

    1. Tyler G. Fenske, John L. McKee, Natalie G. Cavalco, Serena S. Schalk, Emma M. Bonniwell, Josie C. Lammers, Naomi Shacham, Bruna Cuccurazzu, Adam L. Halberstadt, John D. McCorvy. Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design. Journal of Medicinal Chemistry 2025, 68 (19) , 20619-20635. https://doi.org/10.1021/acs.jmedchem.5c01855
    2. Alexander D. Maitland, Nicholas R. Gonzalez, Donna Walther, Francisco Pereira, Michael H. Baumann, Grant C. Glatfelter. Rapid, Open-Source, and Automated Quantification of the Head Twitch Response in C57BL/6J Mice Using DeepLabCut and Simple Behavioral Analysis. ACS Pharmacology & Translational Science 2025, 8 (8) , 2694-2709. https://doi.org/10.1021/acsptsci.5c00305
    3. Clément Delobel, Oz Barnier, Fabien Toulgoat, Thierry Billard. Synthetic Route to Fluoroalkylselenylchalcogeno Molecules. European Journal of Organic Chemistry 2025, 34 https://doi.org/10.1002/ejoc.202500561
    4. Anton V. Yadykov. Methyl 2,2‐difluoro‐2‐(fluorosulfonyl)acetate. 2025, 1-5. https://doi.org/10.1002/047084289X.rn02623
    5. 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
    6. . Discovery of a Potent and Long-Acting Seretonin 5-HT2 Receptor Agonist. Synfacts 2024, 0761. https://doi.org/10.1055/s-0043-1763968
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    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

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