D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J Med Chem 2019 May 09;62(9):4755-4771
Date
04/10/2019Pubmed ID
30964661Pubmed Central ID
PMC6509010DOI
10.1021/acs.jmedchem.9b00508Scopus ID
2-s2.0-85065070718 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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 Gi/o-biased and β-arrestin2-biased D2 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 Gi/o pathway over β-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S1935.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.
Author List
Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, Jin JAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntipsychotic Agents
Dopamine Agonists
Drug Design
Drug Partial Agonism
Female
GTP-Binding Protein alpha Subunits, Gi-Go
HEK293 Cells
Humans
Isoquinolines
Locomotion
Male
Methylurea Compounds
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Structure
Piperazines
Receptors, Dopamine D2
Signal Transduction
Structure-Activity Relationship
beta-Arrestin 2