Structure-functional Selectivity Relationship Studies of β-arrestin-biased Dopamine D₂ Receptor Agonists

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Aug 1

PMID 22845053

Citations 62

Authors

Xin Chen

Maria F Sassano

Lianyou Zheng

Vincent Setola

Meng Chen

Xu Bai

Stephen V Frye

William C Wetsel

Bryan L Roth

Jian Jin

Affiliations

Soon will be listed here.

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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