Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist

• Published in: Molecular pharmacology 2019-11, Vol.96 (5), p.619-628
• Main Authors: Laprairie, Robert B., Vemuri, Kiran, Stahl, Edward L., Korde, Anisha, Ho, Jo-Hao, Grim, Travis W., Hua, Tian, Wu, Yiran, Stevens, Raymond C., Liu, Zhi-Jie, Makriyannis, Alexandros, Bohn, Laura M.
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.119.116483

Cannabinoid receptor 1 (CB1) is a potential therapeutic target for the treatment of pain, obesity and obesity-related metabolic disorders, and addiction. The crystal structure of human CB1 has been determined in complex with the stabilizing antagonist AM6538. In the present study, we characterize AM6538 as a tight-binding/irreversible antagonist of CB1, as well as two derivatives of AM6538 (AM4112 and AM6542) as slowly dissociating CB1 antagonists across binding simulations and cellular signaling assays. The long-lasting nature of AM6538 was explored in vivo wherein AM6538 continues to block CP55,940-mediated behaviors in mice up to 5 days after a single injection. In contrast, the effects of SR141716A abate in mice 2 days after injection. These studies demonstrate the functional outcome of CB1 antagonist modification and open the path for development of long-lasting CB1 antagonists.