合成与评价 1,2,4-三唑并[1,5-c]嘧啶衍生物作为 A2A 受体选择性拮抗剂。
Synthesis and evaluation of 1,2,4-triazolo[1,5-c]pyrimidine derivatives as A2A receptor-selective antagonists.
机构信息
Chemical Biology Unit, Laboratory of Cell Biology and Biochemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8, Rm 121, NIH, NIDDK, LCBB, Bethesda, MD 20892-0810, United States.
出版信息
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5690-4. doi: 10.1016/j.bmcl.2010.08.021. Epub 2010 Aug 10.
Abstract
Movement disorders such as Parkinson's disease and Huntington's disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target the most relevant subtype of adenosine receptors (AR) that are highly expressed in the striatum, that is, the A(2A) AR. To further this goal, we have synthesized and characterized pharmacologically a family of high affinity A(2A) AR ligands, based on the known antagonist, SCH 442416 (R=-Me), which have structural variability on the terminus (R=-Et, -i-Pr, -allyl, and others). A O-fluoroethyl analogue suitable for use as a PET tracer had a K(i) value of 12.4 nM and was highly selective for the A(2A) AR in comparison to the A(1) and A(3) ARs.
摘要
运动障碍，如帕金森病和亨廷顿病，是严重的限制生命和使人衰弱的运动障碍。它们通常发生在从中年到晚年，缺乏有效的诊断技术来检测和跟踪疾病进程。我们的目标是开发用于正电子发射断层扫描（PET）的受体成像剂，这些成像剂选择性地靶向在纹状体中高度表达的最相关的腺苷受体（AR）亚型，即 A(2A)AR。为了进一步实现这一目标，我们已经合成并表征了一系列基于已知拮抗剂 SCH 442416（R=-Me）的高亲和力 A(2A)AR 配体，这些配体在末端具有结构可变性（R=-Et、-i-Pr、-allyl 等）。一种适合用作 PET 示踪剂的 O-氟乙基类似物对 A(2A)AR 的 K(i)值为 12.4 nM，与 A(1)和 A(3)AR 相比，对 A(2A)AR 具有高度选择性。
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本文引用的文献
1
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Neurology. 2011 May 24;76(21):1811-6. doi: 10.1212/WNL.0b013e31821ccce4.
2
Novel Alexa Fluor-488 labeled antagonist of the A(2A) adenosine receptor: Application to a fluorescence polarization-based receptor binding assay.新型 Alexa Fluor-488 标记的 A(2A) 腺苷受体拮抗剂：在基于荧光偏振的受体结合测定中的应用。
Biochem Pharmacol. 2010 Aug 15;80(4):506-11. doi: 10.1016/j.bcp.2010.04.027. Epub 2010 May 11.
3
Novel investigational adenosine A2A receptor antagonists for Parkinson's disease.新型研究用腺苷 A2A 受体拮抗剂治疗帕金森病。
Expert Opin Investig Drugs. 2009 Nov;18(11):1619-31. doi: 10.1517/13543780903241615.
4
Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression.强效高选择性A2A受体拮抗剂普雷拉登特和SCH 412348 [7-[2-[4-(2,4-二氟苯基)-1-哌嗪基]乙基]-2-(2-呋喃基)-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶-5-胺]在运动障碍和抑郁症啮齿动物模型中的特性研究
J Pharmacol Exp Ther. 2009 Jul;330(1):294-303. doi: 10.1124/jpet.108.149617. Epub 2009 Mar 30.
5
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