RT Journal Article SR Electronic T1 Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 619 OP 628 DO 10.1124/mol.119.116483 VO 96 IS 5 A1 Robert B. Laprairie A1 Kiran Vemuri A1 Edward L. Stahl A1 Anisha Korde A1 Jo-Hao Ho A1 Travis W. Grim A1 Tian Hua A1 Yiran Wu A1 Raymond C. Stevens A1 Zhi-Jie Liu A1 Alexandros Makriyannis A1 Laura M. Bohn YR 2019 UL http://molpharm.aspetjournals.org/content/96/5/619.abstract AB 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.