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Synthesis toward bivalent ligands for the dopamine D2 and metabotropic glutamate 5 receptors

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(18). p.8212-8225
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Abstract
In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D-2 receptor (D2R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D2R and mGluR5 compared to cells solely expressing D2R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Addition-ally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D2R and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable D2R and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5-TM6 interface and establishing six protein-ligand H-bonds.
Keywords
ADENOSINE A(2A) RECEPTORS, PROTEIN-COUPLED RECEPTORS, X MENTAL-RETARDATION, BIOLOGICAL EVALUATION, ANXIOLYTIC ACTIVITY, PARKINSONS-DISEASE, AGONIST CHPG, IN-VIVO, POTENT, ANTAGONIST

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Chicago
Qian, Mingcheng, Elise Wouters, James AR Dalton, Martijn Risseeuw, René Crans, Christophe Stove, Jesús Giraldo, Kathleen Van Craenenbroeck, and Serge Van Calenbergh. 2018. “Synthesis Toward Bivalent Ligands for the Dopamine D2 and Metabotropic Glutamate 5 Receptors.” Journal of Medicinal Chemistry 61 (18): 8212–8225.
APA
Qian, M., Wouters, E., Dalton, J. A., Risseeuw, M., Crans, R., Stove, C., Giraldo, J., et al. (2018). Synthesis toward bivalent ligands for the dopamine D2 and metabotropic glutamate 5 receptors. JOURNAL OF MEDICINAL CHEMISTRY, 61(18), 8212–8225.
Vancouver
1.
Qian M, Wouters E, Dalton JA, Risseeuw M, Crans R, Stove C, et al. Synthesis toward bivalent ligands for the dopamine D2 and metabotropic glutamate 5 receptors. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(18):8212–25.
MLA
Qian, Mingcheng, Elise Wouters, James AR Dalton, et al. “Synthesis Toward Bivalent Ligands for the Dopamine D2 and Metabotropic Glutamate 5 Receptors.” JOURNAL OF MEDICINAL CHEMISTRY 61.18 (2018): 8212–8225. Print.
@article{8584572,
  abstract     = {In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D-2 receptor (D2R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D2R and mGluR5 compared to cells solely expressing D2R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Addition-ally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D2R and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable D2R and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5-TM6 interface and establishing six protein-ligand H-bonds.},
  author       = {Qian, Mingcheng and Wouters, Elise and Dalton, James AR and Risseeuw, Martijn and Crans, Ren{\'e} and Stove, Christophe and Giraldo, Jes{\'u}s and Van Craenenbroeck, Kathleen and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  language     = {eng},
  number       = {18},
  pages        = {8212--8225},
  title        = {Synthesis toward bivalent ligands for the dopamine D2 and metabotropic glutamate 5 receptors},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.8b00671},
  volume       = {61},
  year         = {2018},
}

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