D 2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.

Autor: Shen Y; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States., McCorvy JD; 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.; Department of Cell Biology, Neurobiology and Anatomy , Medical College of Wisconsin , Milwaukee , Wisconsin 53226 , United States., Martini ML; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States., Rodriguiz RM; Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology , Duke University Medical Center , Durham , North Carolina 27710 , United States., Pogorelov VM; Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology , Duke University Medical Center , Durham , North Carolina 27710 , United States., Ward KM; Worldwide Research and Development , Internal Medicine Research Unit, Pfizer , Cambridge , Massachusetts 02139 , United States., Wetsel WC; Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology , Duke University Medical Center , Durham , North Carolina 27710 , United States., Liu J; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States., Roth BL; 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., Jin J; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 May 09; Vol. 62 (9), pp. 4755-4771. Date of Electronic Publication: 2019 Apr 18.
DOI: 10.1021/acs.jmedchem.9b00508
Abstrakt: Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G i/o -biased and β-arrestin2-biased D 2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G i/o pathway over β-arrestin2. Unlike the dual D 2 R/D 3 R partial agonist cariprazine, compound 38 showed selective agonist activity for D 2 R over D 3 R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193 5.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D 2 R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D 2 R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.
Databáze: MEDLINE
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