Structure-Functional Selectivity Relationship Studies of β-Arrestin-Biased Dopamine D2 Receptor Agonists

被引：108

作者：

Chen, Xin ^{[1
]}

Sassano, Maria F. ^{[2
,3
]}

Zheng, Lianyou ^{[1
,4
]}

Setola, Vincent ^{[2
,3
]}

Chen, Meng ^{[5
,6
,7
]}

Bai, Xu ^{[4
]}

Frye, Stephen V. ^{[1
]}

Wetsel, William C. ^{[5
,6
,7
]}

Roth, Bryan L. ^{[2
,3
]}

Jin, Jian ^{[1
]}

机构：

[1] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA

[4] Jilin Univ, Ctr Combinatorial Chem & Drug Discovery, Changchun 130012, Jilin, Peoples R China

[5] Duke Univ, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27710 USA

[6] Duke Univ, Dept Cell Biol, Med Ctr, Durham, NC 27710 USA

[7] Duke Univ, Dept Neurobiol, Med Ctr, Durham, NC 27710 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 16期

关键词：

IN-VITRO; ANTIPSYCHOTIC EFFICACY; SIGNAL-TRANSDUCTION; SEROTONIN; ARIPIPRAZOLE; LIGANDS; DERIVATIVES; ANTAGONISTS; ACTIVATION; BINDING;

D O I：

10.1021/jm300603y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 beta-arrestin-biased dopamine D-2 receptor (D2R) 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 beta-arrestin-biased D2R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

引用

页码：7141 / 7153

页数：13

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