Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y(14) Receptor Antagonist Molecular Probes

doi:10.1021/cb500614p

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	Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y(14) Receptor Antagonist Molecular Probes
	Kiselev, Evgeny 3; Barrett, Matthew O.2; Katritch, Vsevolod 1; Paoletta, Silvia 3; Weitzer, Clarissa D.2; Brown, Kyle A.2; Hammes, Eva 3; Yin, Andrew L.3; Zhao, Qiang4 ; Stevens, Raymond C.1
刊名	ACS CHEMICAL BIOLOGY
	2014-12
卷号	9 期号:12 页码:2833-2842
ISSN号	1554-8929
DOI	10.1021/cb500614p
文献子类	Article
英文摘要	The P2Y(14) receptor (P2Y(14)R), one of eight P2Y G protein-coupled receptors (GPCR), is involved in inflammatory, endocrine, and hypoxic processes and is an attractive pharmaceutical target. The goal of this research is to develop high-affinity P2Y(14)R fluorescent probes based on the potent and highly selective antagonist 4-(4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid (6, PPTN). A model of hP2Y(14)R based on recent hP2Y(12)R X-ray structures together with simulated antagonist docking suggested that the piperidine ring is suitable for fluorophore conjugation while preserving affinity. Chain-elongated alkynyl or amino derivatives of 6 for click or amide coupling were synthesized, and their antagonist activities were measured in hP2Y(14)R-expressing CHO cells. Moreover, a new Alexa Fluor 488 (AF488) containing derivative 30 (MRS4174, K-i = 80 pM) exhibited exceptionally high affinity, as compared to 13 nM for the alkyne precursor 22. A flow cytometry assay employing 30 as a fluorescent probe was used to quantify specific binding to P2Y(14)R. Known P2Y receptor ligands inhibited binding of 30 with properties consistent with their previously established receptor selectivities and affinities. These results illustrate that potency in this series of 2-naphthoic acid derivatives can be preserved by chain functionalization, leading to highly potent fluorescent molecular probes for P2Y(14)R. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. This approach demonstrates the predictive power of GPCR homology modeling and the relevance of newly determined X-ray structures to GPCR medicinal chemistry.
资助项目	NIGMS Postdoctoral Research Associate (PRAT) Program[00000000] ; Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases[00000000] ; National Institutes of Health[GM38213] ; National Institutes of Health[U54GM094618]
WOS关键词	HUMAN NEUTROPHILS ; DERIVATIVES ; AGONISTS ; CHEMOTAXIS ; ALKYLATION ; MECHANISM ; ANALOGS ; SCOPE ; DRUG
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000346759600017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276810]
专题	药物靶标结构与功能中心
通讯作者	Jacobson, Kenneth A.
作者单位	1.Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA 2.Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA; 3.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA; 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Kiselev, Evgeny,Barrett, Matthew O.,Katritch, Vsevolod,et al. Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y(14) Receptor Antagonist Molecular Probes[J]. ACS CHEMICAL BIOLOGY,2014,9(12):2833-2842.
APA	Kiselev, Evgeny.,Barrett, Matthew O..,Katritch, Vsevolod.,Paoletta, Silvia.,Weitzer, Clarissa D..,...&Jacobson, Kenneth A..(2014).Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y(14) Receptor Antagonist Molecular Probes.ACS CHEMICAL BIOLOGY,9(12),2833-2842.
MLA	Kiselev, Evgeny,et al."Exploring a 2-Naphthoic Acid Template for the Structure-Based Design of P2Y(14) Receptor Antagonist Molecular Probes".ACS CHEMICAL BIOLOGY 9.12(2014):2833-2842.