Highly Selective Drug-Derived Fluorescent Probes for the Cannabinoid Receptor Type 1 (CB1R)

被引：0

作者：

Mach, Leonard ^{[1
]}

Omran, Anahid ^{[1
]}

Bouma, Jara ^{[2
,3
]}

Radetzki, Silke ^{[1
]}

Sykes, David A. ^{[4
,5
]}

Guba, Wolfgang ^{[6
]}

Li, Xiaoting ^{[7
,8
]}

Hoeffelmeyer, Calvin ^{[1
]}

Hentsch, Axel ^{[1
]}

Gazzi, Thais ^{[1
]}

Mostinski, Yelena ^{[1
]}

Wasinska-Kalwa, Malgorzata ^{[1
]}

de Molnier, Fabio ^{[9
,10
]}

van der Horst, Cas ^{[2
,3
]}

von Kries, Jens Peter ^{[1
]}

Vendrell, Marc ^{[9
,10
]}

Hua, Tian ^{[7
,8
]}

Veprintsev, Dmitry B. ^{[4
,5
]}

Heitman, Laura H. ^{[2
,3
]}

Grether, Uwe ^{[6
]}

Nazare, Marc ^{[1
]}

机构：

[1] Leibniz Forschungsinst Mol Pharmakol FMP, D-13125 Berlin, Germany

[2] Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands

[3] Oncode Inst, NL-2333 CC Leiden, Netherlands

[4] Univ Nottingham, Sch Life Sci, Div Physiol Pharmacol & Neurosci, Nottingham NG7 2UH, England

[5] Univ Birmingham & Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, Midlands, England

[6] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Roche Pharm Res & Early Dev, CH-4070 Basel, Switzerland

[7] ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China

[8] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[9] Univ Edinburgh, Inst Regenerat & Repair, IRR Chem Hub, Edinburgh EH16 4UU, Scotland

[10] Univ Edinburgh, Inst Regenerat & Repair, Ctr Inflammat Res, Edinburgh EH16 4UU, Scotland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 14期

基金：

欧洲研究理事会;

关键词：

HIGH-AFFINITY; ENDOCANNABINOID SYSTEM; PHARMACOLOGY; BINDING; INTERNALIZATION; DISCOVERY; LOCALIZATION; PERMEABILITY; TRAFFICKING; ANTAGONISTS;

D O I：

暂无

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cannabinoid receptor type 1 (CB1R ) is pivotal within the endocannabinoid system regulating various signaling cascades with effects in appetite regulation, pain perception, memory formation, and thermoregulation. Still, understanding of CB1R cellular signaling, distribution, and expression dynamics is very fragmentary. Real-time visualization of CB1R is crucial for addressing these questions. Selective drug-like CB1R ligands with a defined pharmacological profile were investigated for the construction of CB1R fluorescent probes using a reverse design-approach. A modular design concept with a diethyl glycine-based building block as the centerpiece allowed for the straightforward synthesis of novel probe candidates. Validated by computational docking studies, radioligand binding, and cAMP assay, this systematic approach allowed for the identification of novel pyrrole-based CB1R fluorescent probes. Application in fluorescence-based target-engagement studies and live cell imaging exemplify the great versatility of the tailored CB1R probes for investigating CB1R localization, trafficking, pharmacology, and its pathological implications.

引用

页码：11841 / 11867

页数：27

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