Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists. J Med Chem 2019 Apr 11;62(7):3753-3772
Date
03/16/2019Pubmed ID
30875219Pubmed Central ID
PMC6688508DOI
10.1021/acs.jmedchem.9b00351Scopus ID
2-s2.0-85064197112 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Martini ML, Liu J, Ray C, Yu X, Huang XP, Urs A, Urs N, McCorvy JD, Caron MG, Roth BL, Jin JAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCHO Cells
Catechols
Cricetulus
Dopamine Agonists
HEK293 Cells
Humans
Receptors, Dopamine D1
Structure-Activity Relationship
