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.

引用

页数：11

共 50 条

[1] Development of a Bivalent Dopamine D2 Receptor Agonist
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[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (22) : 7911 - 7919
[2] A SUPERPOTENT BIVALENT LIGAND FOR DOPAMINE D2 RECEPTOR HOMODIMERS
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Lopez, L.
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Cordomi, A.
Cortes, A.
Pardo, L.
Royo, M.
Casado, V
[J]. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 2018, 123 : 55 - 56
[3] PET evaluation of the dopamine D2 receptor agonist
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Seneca, N
Gulyas, B
Sovago, J
Farde, L
Innis, RB
Wikstrom, HV
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[4] Bivalent Dopamine D2 Receptor Ligands: Synthesis and Binding Properties
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[5] Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic
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[6] VANADATE INHIBITS AGONIST BINDING TO D2 DOPAMINE RECEPTOR
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FUCHS, S
[J]. JOURNAL OF MOLECULAR NEUROSCIENCE, 1991, 3 (01) : 1 - 6
[7] Identification of xylopropamine as a potential dopamine D2 receptor agonist through computational drug discovery pipeline
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Ugbedeojo, B.
Adoyi, P.
Abah, A.
Onimisi, O.
Musa, S.
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[8] Adenosine A2A Receptor-Antagonist/Dopamine D2 Receptor-Agonist Bivalent Ligands as Pharmacological Tools to Detect A2A-D2 Receptor Heteromers
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Hoen, Rob
Casado, Vicent
Cortes, Antoni
Fanelli, Francesca
Albericio, Fernando
Lluis, Carmen
Franco, Rafael
Royo, Miriam
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (18) : 5590 - 5602
[9] Modeling of Dopamine D2 Receptor and its Agonist DOCK Analyses
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[J]. Journal of Chinese Pharmaceutical Sciences, 1998, (03) : 3 - 8
[10] Aripiprazole acts as a selective dopamine D2 receptor partial agonist
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