PT  - JOURNAL ARTICLE
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
TI  - Probing the CB<sub>1</sub> Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist
AID  - 10.1124/mol.119.116483
DP  - 2019 Nov 01
TA  - Molecular Pharmacology
PG  - 619--628
VI  - 96
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/96/5/619.short
4100  - http://molpharm.aspetjournals.org/content/96/5/619.full
SO  - Mol Pharmacol2019 Nov 01; 96
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.