Synthesis and evaluation of arylpiperazine-reverse amides as biased dopamine D3 receptor ligands

被引：7
作者：
Cao, Yongkai
Paudel, Suresh
Zhang, Xiaowei
Kim, Kyeong-Man [1 ]
Cheon, Seung Hoon
机构：
[1] Chonnam Natl Univ, Coll Pharm, Kwangju 500757, South Korea
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 17期
基金：
新加坡国家研究基金会;
关键词：
Dopamine D3 receptor; Reverse amide; Selectivity; Structure-activity relationships; Molecular modeling; SUBTYPE SELECTIVITY; DISCOVERY; INSIGHTS; COMFA; D2;
D O I：
10.1016/j.bmc.2015.07.072
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The dopamine D3 receptor (D3R) preferential ligands have been universally adopted as a strategy for the treatment of drug addiction and other neuropsychiatric disorders due to fewer side effects. However, the high sequence homology between D3R and the D2 receptor (D2R) challenges the development of D3R-biased compounds. Herein, we design and synthesize a novel series of reverse amide-piperazine hybrid ligands and evaluate their biological affinities in vitro. Compound 4d was found to be the most potent D3R-selective ligand among these hybrid derivatives. Molecular modeling revealed that extracellular loop 1 (EL1) and loop 2 (EL2) of D3R together likely contribute to D3R selectivity over D2R. In particular, Gly94 in EL1 of D3R may act as a molecular determinant for D3R specificity. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5264 / 5272
页数：9
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