Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity

The cannabinoid receptor 1 (CB₁) is a G protein-coupled receptor (GPCR) that is located primarily in the central nervous system. CB₁ is a therapeutic target which may impact pathways to mediate pain, neurodegenerative disorders, hunger, and drug-seeking behavior. Despite these benefits, development of orthosteric therapeutic compounds, which target the endogenous ligand-binding site of CB₁, has been challenging due to detrimental side effects including psychoactivity, depression, and suicidal thoughts. However, CB₁ also has an allosteric binding site(s), which is topographically distinct from the orthosteric site. Allosteric modulation of CB₁ has a number of potential advantages including providing a mechanism for more precise control of downstream pathways and circumventing these side effects. In this review, we summarize the concept of allosteric modulation and focus on the structure-activity relationship studies of the well-characterized allosteric modulators, ORG27569 and PSNCBAM-1 and their derivatives, and a few other recent modulators. We review studies on the properties of these modulators on CB₁ signaling in cells and their effects in vivo. While many current allosteric modulators also produce complex outcomes, they provide new advances for the design of CB₁ centered therapeutics.