Journal
MEDCHEMCOMM
Volume 5, Issue 7, Pages 891-898Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4md00066h
Keywords
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Funding
- Australian Postgraduate Award Industry (APAI)
- Monash University Postgraduate Publication Award
- GSK RD Singapore
- Marie Curie IEF grant
- Interdisciplinary Center for Mathematical and Computational Modelling (ICM), Warsaw, Poland [G30-18]
- CSC, Finland
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Herein, we report the development of novel functionalized congeners of ropinirole toward the design of pharmacological tools to probe structural requirements at the dopamine D-2 receptor. Subsequently, we have used the functionalized amine congener 11 and synthesized and pharmacologically evaluated a series of homobivalent ligands of ropinirole with designated spacer lengths ranging from 14 to 30 atoms. The most potent homobivalent ligands (22-, 26- and 30- atom spacers) showed approximately 20- to 80- fold greater potency (EC50 3.9, 6.2 and 14 nM, respectively) than ropinirole (304 nM) in a [S-35] GTP gamma S functional assay. Molecular modeling studies suggest that the observed increase in potency of the homobivalent ligands is possibly due to a bitopic binding mode involving the orthosteric site and an allosteric interaction at the dopamine D-2 receptor protomer rather than bridging interactions at two orthosteric sites across a dopamine D-2 receptor dimer. This research has the potential to advance the development of structurally related bitopic ligands, biomarkers such as radioligands and fluorescently labeled probes, and furnish new homo- and heterobivalent ligands towards a better understanding of the dopamine D-2 receptor and potential novel treatment for Parkinson's disease.
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