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

Abstract

Cannabidiol (CBD), the second most abundant of the active compounds found in the <i>Cannabis sativa</i> 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.