Abstract
Cannabinoid receptor 1 (CB(1)) is a potential therapeutic target for the treatment of pain, obesity and obesity-related metabolic disorders, and addiction. The crystal structure of human CB(1) has been determined in complex with the stabilizing antagonist AM6538. In the present study, we characterize AM6538 as a tight-binding/irreversible antagonist of CB(1), as well as two derivatives of AM6538 (AM4112 and AM6542) as slowly dissociating CB(1) 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 CB(1) antagonist modification and open the path for development of long-lasting CB(1) antagonists.