- Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists
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G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-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 D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure-functional selectivity relationship study measuring GS and β-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 β-arrestin2 recruitment, while others displayed enhanced GS 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.
- Martini, Michael L.,Liu, Jing,Ray, Caroline,Yu, Xufen,Huang, Xi-Ping,Urs, Aarti,Urs, Nikhil,McCorvy, John D.,Caron, Marc G.,Roth, Bryan L.,Jin, Jian
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p. 3753 - 3772
(2019/04/26)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides thereof; processes and intermediates for preparation of; and compositions and uses thereof. The present invention further provides D1 agonists with reduced D1R desensitization, D1 agonists with a reduced β- arrestin recruitment activity relative to Dopamine, D1 agonists interacting significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R, D1 agonists interacting less strongly with the Asp103 and interacting less strongly with the Ser198 of a D1R when binding to the D1R, and their uses.
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Page/Page column 91; 92; 139
(2014/05/24)
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