Abstract
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.
Footnotes
- Received March 11, 2019.
- Accepted August 17, 2019.
↵1 Current affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
This work was supported by the National Institutes of Health (NIH) National Institutes on Drug Abuse [Grant P01DA009158] (A.M. and L.M.B.) and Grant R37DA023142 (A.M.)]. R.B.L. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research.
This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics