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Structure-functional selectivity relationship studies of ?-arrestin-biased dopamine D? receptor agonists.

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 ?-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 ?-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

SUBMITTER: Chen X 

PROVIDER: S-EPMC3443605 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Chen Xin X   Sassano Maria F MF   Zheng Lianyou L   Setola Vincent V   Chen Meng M   Bai Xu X   Frye Stephen V SV   Wetsel William C WC   Roth Bryan L BL   Jin Jian J  

Journal of medicinal chemistry 20120813 16

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-b  ...[more]

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