Discovery of a true bivalent dopamine D2 receptor agonist

被引：5
|
作者：
Qian, Mingcheng [1 ,2 ]
Ricarte, Adrian [3 ,4 ,5 ]
Wouters, Elise [6 ]
Dalton, James A. R. [3 ,4 ,5 ]
Risseeuw, Martijn D. P. [2 ]
Giraldo, Jesus [3 ,4 ,5 ]
Van Calenbergh, Serge [2 ]
机构：
[1] Changzhou Univ, Sch Pharm, Dept Med Chem, Changzhou 213164, Jiangsu, Peoples R China
[2] Univ Ghent, Lab Med Chem, Ottergemsesteenweg 460, B-9000 Ghent, Belgium
[3] Univ Autonoma Barcelona, Inst Neurociencies, Unitat Bioestadist, Lab Mol Neuropharmacol & Bioinformat, Bellaterra 08193, Spain
[4] Univ Autonoma Barcelona, Ctr Invest Biomed Red Salud Mental, Inst Salud Carlos III, CIBERSAM, Bellaterra 08193, Spain
[5] Univ Autonoma Barcelona, Inst Invest InnovacioParc Tauli I3PT, Inst Neurociencies, Unitat Neurociencia Traslac,Parc Tauli Hosp Univ, Bellaterra 08193, Spain
[6] Univ Ghent, Lab Toxicol, Ottergemsesteenweg 460, B-9000 Ghent, Belgium
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 212卷
关键词：
Bivalent ligands; D2R homodimer; Binding affinity; cAMP; Molecular modeling; LIGANDS; HETEROOLIGOMERS; INHIBITION; INTERFACE; BINDING;
D O I：
10.1016/j.ejmech.2020.113151
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D-2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D-2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D2R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays. (C) 2020 Elsevier Masson SAS. All rights reserved.
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页数：11
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