Discovery of a true bivalent dopamine D2 receptor agonist

Mingcheng Qian; Adrián Ricarte; Elise Wouters; James A.R. Dalton; Martijn D.P. Risseeuw; Jesús Giraldo; Serge Van Calenbergh

doi:10.1016/j.ejmech.2020.113151

Discovery of a true bivalent dopamine D₂ receptor agonist

Mingcheng Qian, Adrián Ricarte, Elise Wouters, James A.R. Dalton, Martijn D.P. Risseeuw, Jesús Giraldo, Serge Van Calenbergh^*

^*Corresponding author for this work

Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health

Research output: Contribution to journal › Article › Research › peer-review

3 Citations (Scopus)

Abstract

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 D₂ receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D₂ 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.

Original language	English
Article number	113151
Journal	European Journal of Medicinal Chemistry
Volume	212
Issue number	15
DOIs	https://doi.org/10.1016/j.ejmech.2020.113151
Publication status	Published - 15 Feb 2021

Keywords

Binding affinity
Bivalent ligands
cAMP
DR homodimer
Molecular modeling

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10.1016/j.ejmech.2020.113151Licence: C In Copyright

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title = "Discovery of a true bivalent dopamine D2 receptor agonist",

abstract = "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 D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 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.",

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AU - Qian, Mingcheng

AU - Ricarte, Adrián

AU - Wouters, Elise

AU - Dalton, James A.R.

AU - Risseeuw, Martijn D.P.

AU - Giraldo, Jesús

AU - Van Calenbergh, Serge

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N2 - 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 D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 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.

AB - 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 D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 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.

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KW - Bivalent ligands

KW - cAMP

KW - DR homodimer

KW - Molecular modeling

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Discovery of a true bivalent dopamine D₂ receptor agonist

Abstract

Keywords

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