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.

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收藏

页码：5264 / 5272

页数：9

相关论文

共 15 条

[1] Design, Synthesis, and Structure-Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity [J].

Ananthan, Subramaniam ;

Saini, Surendra K. ;

Zhou, Guangyan ;

Hobrath, Judith V. ;

Padmalayam, Indira ;

Zhai, Ling ;

Bostwick, J. Robert ;

Antonio, Tamara ;

Reith, Maarten E. A. ;

McDowell, Shea ;

Cho, Eunie ;

McAleer, Leah ;

Taylor, Michelle ;

Luedtke, Robert R. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (16) :7042-7060

[2] N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity [J].

Banala, Ashwini K. ;

Levy, Benjamin A. ;

Khatri, Sameer S. ;

Furman, Cheryse A. ;

Roof, Rebecca A. ;

Mishra, Yogesh ;

Griffin, Suzy A. ;

Sibley, David R. ;

Luedtke, Robert R. ;

Newman, Amy Hauck .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (10) :3581-3594

[3] Dopamine D3 receptor ligands - Recent advances in the control of subtype selectivity and intrinsic activity [J].

Boeckler, Frank ;

Gmeiner, Peter .

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2007, 1768 (04) :871-887

[4] Ligand discovery from a dopamine D3 receptor homology model and crystal structure [J].

Carlsson, Jens ;

Coleman, Ryan G. ;

Setola, Vincent ;

Irwin, John J. ;

Fan, Hao ;

Schlessinger, Avner ;

Sali, Andrej ;

Roth, Bryan L. ;

Shoichet, Brian K. .

NATURE CHEMICAL BIOLOGY, 2011, 7 (11) :769-778

[5] Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist [J].

Chien, Ellen Y. T. ;

Liu, Wei ;

Zhao, Qiang ;

Katritch, Vsevolod ;

Han, Gye Won ;

Hanson, Michael A. ;

Shi, Lei ;

Newman, Amy Hauck ;

Javitch, Jonathan A. ;

Cherezov, Vadim ;

Stevens, Raymond C. .

SCIENCE, 2010, 330 (6007) :1091-1095

[6] A general and convenient synthesis of N-aryl piperazines [J].

Liu, KG ;

Robichaud, AJ .

TETRAHEDRON LETTERS, 2005, 46 (46) :7921-7922

[7] A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors [J].

Michino, Mayako ;

Donthamsetti, Prashant ;

Beuming, Thijs ;

Banala, Ashwini ;

Duan, Lihua ;

Roux, Thomas ;

Han, Yang ;

Trinquet, Eric ;

Newman, Amy Hauck ;

Javitch, Jonathan A. ;

Shi, Lei .

MOLECULAR PHARMACOLOGY, 2013, 84 (06) :854-864

[8] Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents [J].

Miyamoto, S. ;

Miyake, N. ;

Jarskog, L. F. ;

Fleischhacker, W. W. ;

Lieberman, J. A. .

MOLECULAR PSYCHIATRY, 2012, 17 (12) :1206-1227

[9] Functionally Selective Dopamine D2, D3 Receptor Partial Agonists [J].

Moeller, Dorothee ;

Kling, Ralf C. ;

Skultety, Marika ;

Leuner, Kristina ;

Huebner, Harald ;

Gmeiner, Peter .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (11) :4861-4875

[10] Molecular Determinants of Selectivity and Efficacy at the Dopamine D3 Receptor [J].

Newman, Amy Hauck ;

Beuming, Thijs ;

Banala, Ashwini K. ;

Donthamsett, Prashant ;

Pongetti, Katherine ;

LaBounty, Alex ;

Levy, Benjamin ;

Cao, Jianjing ;

Michino, Mayako ;

Luedtke, Robert R. ;

Javitch, Jonathan A. ;

Shi, Lei .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (15) :6689-6699