How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1
Farsheed Shahbazi-Raz, Daniel Meister, Azam Mohammadzadeh, J. Trant
iScience May 1, 2025 DOI: 10.1016/j.isci.2025.112706 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or computational modeling paper Peer reviewed |
|---|---|
| Topics | Cannabis |
| Key points | Proposes a membrane-partition-corrected method for calculating ligand affinity at the CB1 orthosteric site and uses it to assign predicted high and low affinities to cannabinoids. Argues that a mechanism for THC partial agonism arises from the model and is consistent with experimental data. |
Abstract
Summary Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data.
Comparable studies
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| Delta-8, Delta-10, HHC, THC-O, THCP, and THCV: What Should We Call These Products? | 2023 | Theoretical or philosophical paper | |
| Model Psychoses Induced by LSD-25 in Normals | 1956 | Historical analysis | |
| Is there a specific ‘cannabis psychosis’? | 2004 | Theoretical or philosophical paper | |
| Peak-experience and the entheogenic use of cannabis in world religions | 2021 | Theoretical or philosophical paper | |
| Out of Harm's Way?: Illicit Drug Use, Medicalization and the Law | 2003 | Theoretical or philosophical paper |
Citations in the library
Cites 3
- Structural basis of THC analog activity at the Cannabinoid 1 receptor Nature Communications January 8, 2025
- The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British Journal of Pharmacology January 2008
- A novel probe for the cannabinoid receptor. Journal of Medicinal Chemistry May 29, 1992