Probing the CB1 cannabinoid receptor binding pocket with AM6538, a high-affinity irreversible antagonist

Robert B. Laprairie; Kiran Vemuri; Edward L. Stahl; Anisha Korde; Jo Hao Ho; Travis W. Grim; Tian Hua; Yiran Wu; Raymond C. Stevens; Zhi Jie Liu; Alexandros Makriyannis; Laura M. Bohn

doi:10.1124/mol.119.116483

Probing the CB₁ cannabinoid receptor binding pocket with AM6538, a high-affinity irreversible antagonist

Robert B. Laprairie, Kiran Vemuri, Edward L. Stahl, Anisha Korde, Jo Hao Ho, Travis W. Grim, Tian Hua, Yiran Wu, Raymond C. Stevens, Zhi Jie Liu, Alexandros Makriyannis, Laura M. Bohn

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

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.

Original language	English
Pages (from-to)	619-628
Number of pages	10
Journal	Molecular Pharmacology
Volume	96
Issue number	5
DOIs	https://doi.org/10.1124/mol.119.116483
Publication status	Published - Nov 2019
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding Information:
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. 1Current affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada. https://doi.org/10.1124/mol.119.116483. s This article has supplemental material available at molpharm. aspetjournals.org.

Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

ASJC Scopus Subject Areas

Molecular Medicine
Pharmacology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1124/mol.119.116483

Cite this

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title = "Probing the CB1 cannabinoid receptor binding pocket with AM6538, a high-affinity irreversible antagonist",

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.",

author = "Laprairie, {Robert B.} and Kiran Vemuri and Stahl, {Edward L.} and Anisha Korde and Ho, {Jo Hao} and Grim, {Travis W.} and Tian Hua and Yiran Wu and Stevens, {Raymond C.} and Liu, {Zhi Jie} and Alexandros Makriyannis and Bohn, {Laura M.}",

note = "Funding Information: 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. Funding Information: 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. 1Current affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada. https://doi.org/10.1124/mol.119.116483. s This article has supplemental material available at molpharm. aspetjournals.org. Publisher Copyright: Copyright {\textcopyright} 2019 by The American Society for Pharmacology and Experimental Therapeutics.",

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AU - Korde, Anisha

AU - Ho, Jo Hao

AU - Grim, Travis W.

AU - Hua, Tian

AU - Wu, Yiran

AU - Stevens, Raymond C.

AU - Liu, Zhi Jie

AU - Makriyannis, Alexandros

AU - Bohn, Laura M.

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