1. D 2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.
- Author
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Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, and Jin J
- Subjects
- Animals, Antipsychotic Agents chemical synthesis, Antipsychotic Agents metabolism, Antipsychotic Agents pharmacology, Dopamine Agonists chemical synthesis, Dopamine Agonists metabolism, Drug Design, Drug Partial Agonism, Female, HEK293 Cells, Humans, Isoquinolines chemical synthesis, Isoquinolines metabolism, Locomotion drug effects, Male, Methylurea Compounds chemical synthesis, Methylurea Compounds metabolism, Mice, Inbred C57BL, Molecular Docking Simulation, Molecular Structure, Piperazines chemistry, Receptors, Dopamine D2 metabolism, Signal Transduction drug effects, Structure-Activity Relationship, beta-Arrestin 2 metabolism, Dopamine Agonists pharmacology, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Isoquinolines pharmacology, Methylurea Compounds pharmacology, Receptors, Dopamine D2 agonists
- Abstract
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 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 D2 R/D3 R partial agonist cariprazine, compound 38 showed selective agonist activity for D2 R over D3 R. 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 D2 R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2 R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.- Published
- 2019
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