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Structural basis of THC analog activity at the Cannabinoid 1 receptor

Author

Listed:
  • Thor S. Thorsen

    (University of Copenhagen
    BioInnovation Institute)

  • Yashraj Kulkarni

    (University of Copenhagen)

  • David A. Sykes

    (University of Nottingham
    University of Nottingham)

  • Andreas Bøggild

    (Aarhus University)

  • Taner Drace

    (Aarhus University)

  • Pattarin Hompluem

    (University of Nottingham
    University of Nottingham)

  • Christos Iliopoulos-Tsoutsouvas

    (Northeastern University)

  • Spyros P. Nikas

    (Northeastern University)

  • Henrik Daver

    (University of Copenhagen
    H. Lundbeck A/S)

  • Alexandros Makriyannis

    (Northeastern University
    Northeastern University)

  • Poul Nissen

    (Aarhus University
    Danish Research Institute of Translational Neuroscience – DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Denmark)

  • Michael Gajhede

    (University of Copenhagen)

  • Dmitry B. Veprintsev

    (University of Nottingham
    University of Nottingham)

  • Thomas Boesen

    (Aarhus University
    Danish Research Institute of Translational Neuroscience – DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Denmark)

  • Jette S. Kastrup

    (University of Copenhagen)

  • David E. Gloriam

    (University of Copenhagen)

Abstract

Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.

Suggested Citation

  • Thor S. Thorsen & Yashraj Kulkarni & David A. Sykes & Andreas Bøggild & Taner Drace & Pattarin Hompluem & Christos Iliopoulos-Tsoutsouvas & Spyros P. Nikas & Henrik Daver & Alexandros Makriyannis & Po, 2025. "Structural basis of THC analog activity at the Cannabinoid 1 receptor," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55808-4
    DOI: 10.1038/s41467-024-55808-4
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    References listed on IDEAS

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