D2 Dopamine Receptor G protein-biased Partial Agonists Based on Cariprazine.

08:00 EDT 9th April 2019 | BioPortfolio

Summary of "D2 Dopamine Receptor G protein-biased Partial Agonists Based on Cariprazine."

Functionally selective G protein-coupled receptor (GPCR) 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 FDA approved drug aripiprazole. In this work, based on another FDA approved drug, cariprazine, we conducted a structure-functional selectivity relationship (SFSR) 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 (EL2), 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 (PCP)-induced hyperlocomotion.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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