Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 7, Pages 3753-3772Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00351
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Funding
- U.S. National Institutes of Health [RO1NS100930, U24DK116195]
- NIGMS [T32 GM062754]
- MSTP training grants at the Icahn School of Mount Sinai [NIH T32 GM007280]
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G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as beta-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D-1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring G(s) and beta-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse functional selectivity profiles. Some compounds became potent full agonists of beta-arrestin2 recruitment, while others displayed enhanced G(s) bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered functional selectivity profile demonstrated excellent blood-brain barrier penetration. This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of biased D1R ligands.
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