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首页> 外文期刊>Biochemistry >Structure-Based Design, Synthesis, and Biochemical and Pharmacological Characterization of Novel Salvinorin A Analogues as Active State Probes of the κ-Opioid Receptor
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Structure-Based Design, Synthesis, and Biochemical and Pharmacological Characterization of Novel Salvinorin A Analogues as Active State Probes of the κ-Opioid Receptor

机译：新型Salvinorin A类似物作为κ阿片受体的活性状态探针的基于结构的设计，合成以及生化和药理学表征

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Salvinorin A, the most potent naturally occurring hallucinogen, has attracted an increasingnamount of attention since the κ-opioid receptor (KOR) was identified as its principal molecular target by usn[Roth, B. L., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 11934-11939]. Here we report the design, synthesis,nand biochemical characterization of novel, irreversible, salvinorin A-derived ligands suitable as active statenprobes of the KOR. On the basis of prior substituted cysteine accessibility and molecular modeling studies,nC3157.38 was chosen as a potential anchoring point for covalent labeling of salvinorin A-derived ligands.nAutomated docking of a series of potential covalently bound ligands suggested that either a haloacetatenmoiety or other similar electrophilic groups could irreversibly bind with C3157.38. 22-ThiocyanatosalvinorinnA (RB-64) and 22-chlorosalvinorin A (RB-48) were both found to be extraordinarily potent and selectivenKOR agonists in vitro and in vivo. As predicted on the basis of molecular modeling studies, RB-64 inducednwash-resistant inhibition of binding with a strict requirement for a free cysteine in or near the binding pocket.nMass spectrometry (MS) studies utilizing synthetic KOR peptides and RB-64 supported the hypothesis thatnthe anchoring residue was C3157.38 and suggested one biochemical mechanism for covalent binding. Thesenstudies provide direct evidence of the presence of a free cysteine in the agonist-bound state of the KOR andnprovide novel insights into the mechanism by which salvinorin A binds to and activates the KOR.
机译：Salvinorin A是最有效的天然致幻剂，自从USn确认κ阿片受体（KOR）是其主要分子靶标以来，它就引起了越来越多的关注。[Roth，B. L.，et al。 （2002年）过程。 Natl。学院科学美国，99，11934-11939]。在这里，我们报告适用于KOR活性状态探针的新型，不可逆的Salvinorin A衍生的配体的设计，合成，及其生化特性。在先前的取代半胱氨酸可及性和分子建模研究的基础上，选择nC3157.38作为Salvinorin A衍生的配体进行共价标记的潜在锚点。n一系列潜在的共价结合配体的自动对接表明，卤代乙酸盐部分或其他类似的亲电子基团可能不可逆地与C3157.38结合。在体外和体内，发现22-硫氰酸根合沙门氏菌素A（RB-64）和22-氯水杨酸结合素A（RB-48）都是非常有效的选择性nKOR激动剂。正如根据分子模型研究预测的那样，RB-64诱导了结合耐洗涤性的抑制，并严格要求结合口袋中或附近有游离半胱氨酸。利用合成KOR肽和RB-64的n质谱（MS）研究支持假说锚定残基为C3157.38，提示共价结合的一种生化机制。这些研究提供了在KOR激动剂结合状态下游离半胱氨酸的存在的直接证据，并提供了新的见解来说明Salvinorin A结合并激活KOR的机理。

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