Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist

doi:10.1124/mol.119.116483

	Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist
	Laprairie, Robert B.1,2,9; Vemuri, Kiran 3,4,5; Stahl, Edward L.1,2; Korde, Anisha 3,4,5; Ho, Jo-Hao 1,2; Grim, Travis W.1,2; Hua, Tian6 ; Wu, Yiran6 ; Stevens, Raymond C.7,8; Liu, Zhi-Jie6 ; Makriyannis, Alexandros 3,4,5; Bohn, Laura M.1,2
	2019-11
发表期刊	MOLECULAR PHARMACOLOGY (IF:3.2[JCR-2023],3.5[5-Year])
ISSN	0026-895X
卷号	96 期号:5 页码:619-628
发表状态	已发表
DOI	10.1124/mol.119.116483
摘要	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.
收录类别	SCI ; SCIE
语种	英语
资助项目	National Institutes of Health (NIH) National Institutes on Drug Abuse[P01DA009158] ; National Institutes of Health (NIH) National Institutes on Drug Abuse[R37DA023142]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Pharmacology & Pharmacy
WOS记录号	WOS:000490862800011
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS关键词	ENDOCANNABINOID SYSTEM ; CRYSTAL-STRUCTURE ; ACCURATE DOCKING ; RESIDENCE TIME ; POTENT ; GLIDE ; PHARMACOLOGY ; RIMONABANT ; MECHANISM ; SR141716A
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/80387
专题	iHuman研究所_PI研究组_刘志杰组 iHuman研究所_PI研究组_赵素文组 iHuman研究所_PI研究组_华甜组
通讯作者	Bohn, Laura M.
作者单位	1.Scripps Res Inst, Dept Mol Med, 130 Scripps Way 2A2, Jupiter, FL 33458 USA 2.Scripps Res Inst, Dept Neurosci, 130 Scripps Way 2A2, Jupiter, FL 33458 USA 3.Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA 4.Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA 5.Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA 6.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 7.Univ Southern Calif, Dept Biol Sci, Bridge Inst, Michelson Ctr Convergent Biosci, Los Angeles, CA 90089 USA 8.Univ Southern Calif, Dept Chem, Bridge Inst, Michelson Ctr Convergent Biosci, Los Angeles, CA 90089 USA 9.Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK, Canada
推荐引用方式 GB/T 7714	Laprairie, Robert B.,Vemuri, Kiran,Stahl, Edward L.,et al. Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist[J]. MOLECULAR PHARMACOLOGY,2019,96(5):619-628.
APA	Laprairie, Robert B..,Vemuri, Kiran.,Stahl, Edward L..,Korde, Anisha.,Ho, Jo-Hao.,...&Bohn, Laura M..(2019).Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist.MOLECULAR PHARMACOLOGY,96(5),619-628.
MLA	Laprairie, Robert B.,et al."Probing the CB1 Cannabinoid Receptor Binding Pocket with AM6538, a High-Affinity Irreversible Antagonist".MOLECULAR PHARMACOLOGY 96.5(2019):619-628.