Chromenopyrazole-based High Affinity, Selective Fluorescent Ligands for Cannabinoid Type 2 Receptor

被引：31
|
作者：
Singh, Sameek [1 ]
Oyagawa, Caitlin R. M. [2 ,3 ]
Macdonald, Christa [2 ,3 ]
Grimsey, Natasha L. [2 ,3 ]
Glass, Michelle [2 ,3 ,4 ]
Vernall, Andrea J. [1 ]
机构：
[1] Univ Otago, Sch Pharm, Dunedin, New Zealand
[2] Univ Auckland, Sch Med Sci, Dept Pharmacol & Clin Pharmacol, Fac Med & Hlth Sci, Auckland, New Zealand
[3] Univ Auckland, Sch Med Sci, Ctr Brain Res, Fac Med & Hlth Sci, Auckland, New Zealand
[4] Univ Otago, Dept Pharmacol & Toxicol, Dunedin 9016, New Zealand
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 02期
关键词：
GPCR; cannabinoid type 2 receptor; fluorescent ligand; chemical tool; CB2; RECEPTOR; ENDOCANNABINOID SYSTEM; SCAFFOLD; AGONISTS; PROBES; TOOLS;
D O I：
10.1021/acsmedchemlett.8b00597
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Cannabinoid type 2 receptor (CB2R) is an attractive target for the treatment of pain and inflammatory disorders. Availability of a selective CB2R fluorescent ligand to study CB2R expression and localization in healthy and disease conditions would greatly contribute to improving our understanding of this receptor. Herein, we report a series of chromenopyrazole-based CB2R fluorescent ligands. The highest affinity fluorescent ligand was Cy5-containing 24 (hCB(2)R pK(i), = 7.38 +/- 0.05), which had 131-fold selectivity over CB1R. In a cAMP BRET assay, 24 behaved as a potent CB2R. inverse agonist. Widefield imaging experiments showed that 24 binds to CB2R in live cells with good selectivity and low levels of nonspecific fluorescence. The high affinity, selectivity, and suitable imaging properties of fluorescent ligand 24 make it a valuable tool for studying CB2R.
引用
收藏
页码：209 / 214
页数：11
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