Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D2-Like Receptors and the -Opioid Receptor

被引：22

作者：

Qian, Mingcheng ^{[1
,2
]}

Vasudevan, Lakshmi ^{[2
]}

Huysentruyt, Jelle ^{[2
]}

Risseeuw, Martijn D. P. ^{[1
]}

Stove, Christophe ^{[2
]}

Vanderheyden, Patrick M. L. ^{[3
]}

Van Craenenbroeck, Kathleen ^{[2
]}

Van Calenbergh, Serge ^{[1
]}

机构：

[1] Univ Ghent, Lab Med Chem, Ottergemsesteenweg 460, B-9000 Ghent, Belgium

[2] Univ Ghent, Lab Toxicol, Ottergemsesteenweg 460, Ghent, Belgium

[3] Vrije Univ Brussel, Fac Sci & Bioengn Sci, Dept Res Grp Mol & Biochem Pharmacol, VUB MBFA, Pl Laan 2, B-1050 Brussels, Belgium

来源：

CHEMMEDCHEM | 2018年 / 13卷 / 09期

关键词：

bivalent ligands; dopamine D-2-like receptors; ligand binding; signal transduction; -opioid receptors; AGONIST; ANTAGONIST; EXPRESSION; BINDING; D2; PHARMACOPHORES; UBIQUITINATION; DIMERIZATION; MODULATION; AFFINITY;

D O I：

10.1002/cmdc.201700787

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Currently, there is mounting evidence that intermolecular receptor-receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful as molecular probes for confirming and targeting heteromeric receptors. This report describes the design and synthesis of novel heterobivalent ligands for dopamine D-2-like receptors (D-2-likeR) and the -opioid receptor (OR) and their evaluation using ligand binding and functional assays. Interestingly, we identified a potent bivalent ligand that contains a short 18-atom linker and combines good potency with high efficacy both in -arrestin2 recruitment for OR and MAPK-P for D4R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D4R-OR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D4R-OR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D4R and OR.

引用

页码：944 / 956

页数：13

共 42 条

[1] An easy access to asymmetrically substituted oligoethylene glycols from 18-crown-6 [J].