Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists.
Biased ligands (also known as functionally selective ligands) of G protein-coupled receptors are valuable tools for dissecting the roles of G protein-dependent and independent signaling pathways in health and disease. Biased ligands have also been increasingly pursued by the biomedical community as promising therapeutics with improved efficacy and reduced side effects compared with unbiased ligands. We previously discovered first-in-class β-arrestin-biased agonists of dopamine D2 receptor (D2R) by extensively exploring multiple regions of aripiprazole, a balanced D2R agonist. In our continuing efforts to identify biased agonists of D2R, we unexpectedly discovered a G protein-biased agonist of D2R, compound 1, which is the first G protein-biased D2R agonist from the aripiprazole scaffold. We designed and synthesized novel analogues to explore two regions of 1 and conducted structure-functional selectivity relationship (SFSR) studies. Here we report the discovery of 1, findings from our SFSR studies, and characterization of novel G protein-biased D2R agonists.
Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029, United States.
Xin
X
Chen
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
John D
JD
McCorvy
Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029, United States.
Matthew G
MG
Fischer
Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029, United States.
Kyle V
KV
Butler
Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029, United States.
Yudao
Y
Shen
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Bryan L
BL
Roth
Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029, United States.
Jian
J
Jin
D000068180:Aripiprazole / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013329:Structure-Activity Relationship
C581293:DRD2 protein, human; D008024:Ligands; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D019204:GTP-Binding Proteins