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^*

^*Autor corresponent d’aquest treball

Departament de Pediatria, d’Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública

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Resum

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.

Idioma original	Anglès
Número d’article	113151
Revista	European Journal of Medicinal Chemistry
Volum	212
Número	15
DOIs	https://doi.org/10.1016/j.ejmech.2020.113151
Estat de la publicació	Publicada - 15 de febr. 2021

Accés al document

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

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Com citar-ho

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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.",

keywords = "Binding affinity, Bivalent ligands, cAMP, DR homodimer, Molecular modeling",

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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

PY - 2021/2/15

Y1 - 2021/2/15

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.

KW - Binding affinity

KW - Bivalent ligands

KW - cAMP

KW - DR homodimer

KW - Molecular modeling

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