Recent structural studies of the cannabinoid receptor 1 (CB1R) have shed light on the binding mechanisms of two novel peripheral inverse agonists, MRI-1867 and MRI-1891. These findings may pave the way for safer treatments for obesity and other metabolic disorders.
CB1R, widely expressed throughout the brain and peripheral tissues, plays a key role in regulating neurotransmission and metabolism. While previous brain-penetrant CB1R antagonists demonstrated efficacy for weight loss, they also produced significant psychiatric side effects, most notoriously associated with rimonabant, which was withdrawn from the market after approval due to suicidality risks.
Emerging from this backdrop, MRI-1867 and MRI-1891 were developed to selectively target peripheral CB1R signaling. By restricting activity to outside the central nervous system, these compounds aim to provide metabolic benefits without adverse psychological effects. A collaborative effort between researchers employed advanced cryo-electron microscopy (cryo-EM) to visualize the inactive state of the receptor when complexed with these two compounds, yielding insight on their unique binding behaviors.
The study confirmed MRI-1867 and MRI-1891 maintain high affinity for CB1R's orthosteric site, with MRI-1891 displaying biased inhibition particularly toward β-arrestin signaling. These observations provide evidence of differing pathways for drug efficacy, potentially translating to enhanced therapeutic benefits.
“These structural insights suggest how receptor dynamics can be tuned for specific therapeutic outcomes,” the authors of the article remarked, emphasizing the need for targeted drug design to minimize side effects.
Detailed binding interactions revealed how these ligands influence receptor conformation. MRI-1891 engages with transmembrane helices to exert its signaling bias, which researchers believe is key to its reduced propensity for adverse CNS effects. The design of MRI-1891 includes polar functional groups which facilitate its interaction with CB1R without breaching the blood-brain barrier, exemplifying progress toward creating safer anti-obesity treatments.
Former methods struggled to capture inactive GPCR structures, making this advancement significant. By implementing specialized nanobody technology fused with the receptor, the researchers achieved unprecedented resolution, adding clarity to our molecular comprehension of this prominent receptor family.
The importance of this work cannot be overstated, as the search for peripherally selective CB1R agents may lead to safer medications for obesity and other metabolic disorders. The research suggests future studies can build on these findings, exploring how modifications to existing compounds can yield diverse therapeutic profiles.
The next steps involve extensive translational studies to verify efficacy and safety profiles for these novel compounds, and explore their potential for broader therapeutic applications beyond weight management.
