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Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists. | LitMetric

Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists.

J Med Chem

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Published: August 2012

AI Article Synopsis

Article Abstract

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first β-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443605PMC
http://dx.doi.org/10.1021/jm300603yDOI Listing

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