%0 Journal Article %A Robert B. Laprairie %A Kiran Vemuri %A Edward L. Stahl %A Anisha Korde %A Jo-Hao Ho %A Travis W. Grim %A Tian Hua %A Yiran Wu %A Raymond C. Stevens %A Zhi-Jie Liu %A Alexandros Makriyannis %A Laura M. Bohn %T Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist %D 2019 %R 10.1124/mol.119.116483 %J Molecular Pharmacology %P 619-628 %V 96 %N 5 %X 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. %U https://molpharm.aspetjournals.org/content/molpharm/96/5/619.full.pdf