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Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

  • Michael J. Cunningham
    Michael J. Cunningham
    Department of Chemistry, Columbia University, New York, New York 10027, United States
  • Hailey A. Bock
    Hailey A. Bock
    Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
  • Inis C. Serrano
    Inis C. Serrano
    Department of Chemistry, Columbia University, New York, New York 10027, United States
  • Benjamin Bechand
    Benjamin Bechand
    Department of Chemistry, Columbia University, New York, New York 10027, United States
  • D. J. Vidyadhara
    D. J. Vidyadhara
    Department of Neuroscience, Department of Neurology, Yale University, New Haven, Connecticut 06510, United States
  • Emma M. Bonniwell
    Emma M. Bonniwell
    Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
  • David Lankri
    David Lankri
    Department of Chemistry, Columbia University, New York, New York 10027, United States
    More by David Lankri
  • Priscilla Duggan
    Priscilla Duggan
    Department of Neuroscience, Barnard College, New York, New York 10027, United States
  • Antonina L. Nazarova
    Antonina L. Nazarova
    Department of Quantitative and Computational Biology, Department of Chemistry, Dornsife Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California 90089, United States
  • Andrew B. Cao
    Andrew B. Cao
    Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
  • Maggie M. Calkins
    Maggie M. Calkins
    Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
  • Prashant Khirsariya
    Prashant Khirsariya
    Department of Chemistry, Columbia University, New York, New York 10027, United States
  • Christopher Hwu
    Christopher Hwu
    Department of Chemistry, Columbia University, New York, New York 10027, United States
  • Vsevolod Katritch
    Vsevolod Katritch
    Department of Quantitative and Computational Biology, Department of Chemistry, Dornsife Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California 90089, United States
  • Sreeganga S. Chandra
    Sreeganga S. Chandra
    Department of Neuroscience, Department of Neurology, Yale University, New Haven, Connecticut 06510, United States
  • John D. McCorvy*
    John D. McCorvy
    Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States
    *Email: [email protected]
  • , and 
  • Dalibor Sames*
    Dalibor Sames
    Department of Chemistry, and Zuckerman Institute of Mind, Brain, Behavior, Columbia University, New York, New York 10027, United States
    *Email: [email protected]
Cite this: ACS Chem. Neurosci. 2023, 14, 1, 119–135
Publication Date (Web):December 15, 2022
https://doi.org/10.1021/acschemneuro.2c00597
Copyright © 2022 American Chemical Society

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    Abstract

    Abstract Image

    Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson’s disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and β-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson’s disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne’s lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

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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/acschemneuro.2c00597.

    • Synthesis and characterization of compounds used in this study, additional in vitro and in vivo figures, and experimental details (PDF)

    • Balance beam test used to assess fine motor skills by evaluating the ability of mice to walk on a raised narrow beam to reach a safety box (MP4)

    • Hind limb clasping score and the total duration clasping (MP4)

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    Cited By

    This article is cited by 9 publications.

    1. Richard A. Glennon, Małgorzata Dukat. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review. ACS Pharmacology & Translational Science 2024, Article ASAP.
    2. Grant C. Glatfelter, Eline Pottie, John S. Partilla, Christophe P. Stove, Michael H. Baumann. Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. ACS Pharmacology & Translational Science 2024, 7 (3) , 641-653. https://doi.org/10.1021/acsptsci.3c00192
    3. Wenwen Duan, Dongmei Cao, Sheng Wang, Jianjun Cheng. Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants. Chemical Reviews 2024, 124 (1) , 124-163. https://doi.org/10.1021/acs.chemrev.3c00375
    4. Richard A. Glennon, Mal̵gorzata Dukat. α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant. ACS Pharmacology & Translational Science 2023, 6 (12) , 1780-1789. https://doi.org/10.1021/acsptsci.3c00139
    5. Andrew A. BolingerNoelle C. AnastasioKathryn A. CunninghamJia Zhou. THE SEROTONIN 5-HT2A RECEPTOR AS AN EVOLVING NEUROTHERAPEUTIC TARGET. , 53-81. https://doi.org/10.1021/mc-2023-vol58.ch03
    6. Eline Pottie, Christian B. M. Poulie, Icaro A. Simon, Kasper Harpsøe, Laura D’Andrea, Igor V. Komarov, David E. Gloriam, Anders A. Jensen, Jesper L. Kristensen, Christophe P. Stove. Structure–Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists. ACS Chemical Neuroscience 2023, 14 (15) , 2727-2742. https://doi.org/10.1021/acschemneuro.3c00267
    7. Andreas B. Wulff, Charles D. Nichols, Scott M. Thompson. Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders. Neuropharmacology 2023, 231 , 109504. https://doi.org/10.1016/j.neuropharm.2023.109504
    8. Ryan H. Gumpper, Bryan L. Roth. Psychedelics: preclinical insights provide directions for future research. Neuropsychopharmacology 2023, 68 https://doi.org/10.1038/s41386-023-01567-7
    9. D.J. Vidyadhara, Mahalakshmi Somayaji, Nigel Wade, Betül Yücel, Helen Zhao, N. Shashaank, Joseph Ribaudo, Jyoti Gupta, TuKiet T. Lam, Dalibor Sames, Lois E. Greene, David L. Sulzer, Sreeganga S. Chandra. Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease. Cell Reports 2023, 42 (3) , 112231. https://doi.org/10.1016/j.celrep.2023.112231

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