Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2 Receptor Derived from the Natural Product Cannabidiol

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

Automated summary

Cannabidiol (CBD), the second most abundant active compound in the Cannabis sativa plant, is gaining interest for its potential human use as it is neither euphorizing nor addictive. Researchers have designed and synthesized novel compounds based on CBD's properties as a partial agonist and negative allosteric modulator, offering potential therapeutic utility for the cannabinoid CB2 receptor. By using molecular dynamic simulations and site-directed mutagenesis studies, they have identified the allosteric site near the receptor entrance, allowing for structure-guided design of CB2 receptor modulators.