TY - JOUR T1 - Probing the CB<sub>1</sub> Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist JF - Molecular Pharmacology JO - Mol Pharmacol SP - 619 LP - 628 DO - 10.1124/mol.119.116483 VL - 96 IS - 5 AU - Robert B. Laprairie AU - Kiran Vemuri AU - Edward L. Stahl AU - Anisha Korde AU - Jo-Hao Ho AU - Travis W. Grim AU - Tian Hua AU - Yiran Wu AU - Raymond C. Stevens AU - Zhi-Jie Liu AU - Alexandros Makriyannis AU - Laura M. Bohn Y1 - 2019/11/01 UR - http://molpharm.aspetjournals.org/content/96/5/619.abstract N2 - 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. ER -