Modification of Salvinorin A and the influence on its binding affinity to the human kappa opioid receptor

Salvinorin A的修饰及其对人κ阿片受体结合亲和力的影响

• 批准号: 355558520
• 负责人: Dr. Lucilla Levi
• 金额: --
• 依托单位: Department of Chemistry and Biochemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/355558520?language=en
• 关键词: Modification; Salvinorin; influence; its; binding

Opioids are a well-known class of psychoactive natural, semi-synthetic or synthetic compounds with pain relieving and sedative properties. The most popular naturally encountered opioid is morphine, which shows extremely high activity but has the severe side-effect of provoking strong addictions. In the human body, the pharmacological effects of opioids are mediated by opioid receptors, which are divided into three major classes. It was proven that strong addiction to these drugs arises when two of the classes of opioid receptors are addressed.Salvinorin A is a naturally occurring compound with psychoactive properties that induces pain-relief without causing addiction, since it only stimulates the third class of opioid receptors. The structure and stereochemistry as well as the binding mode to the opioid receptor have been studied and clarified with different methods. Nevertheless, the exact effects of this drug are not deeply understood, so that the synthesis of modified analogs is required. The modifications should also allow to find more potent species. This project concentrates on the synthesis of diverse analogs of Salvinorin A by modifying one of the binding positions of the molecule. The activity and the binding mode of the synthesized analogs will be tested in cooperation with pharmacologists. Computational studies will complete the work.This project will not only provide a deeper understanding of the binding mode of Salvinorin A and its analogs. Novel and efficient synthetic strategies introduced for this natural product could also be applied in the preparation of other natural products. The knowledge obtained here will be transferable to similar drugs, contributing to a more rational drug design of powerful analgesics.

阿片样物质是一类众所周知的具有镇痛和镇静特性的精神活性天然、半合成或合成化合物。最受欢迎的自然遇到的阿片类药物是吗啡，它显示出极高的活性，但具有引发强烈成瘾的严重副作用。在人体内，阿片类药物的药理作用是由阿片受体介导的，阿片受体分为三大类。已证明，当两类阿片受体被处理时，对这些药物的强烈成瘾就会产生。鼠尾草素A是一种天然存在的化合物，具有精神活性，可以缓解疼痛而不会导致成瘾，因为它只刺激第三类阿片受体。用不同的方法研究了它的结构、立体化学以及与阿片受体的结合方式。然而，这种药物的确切作用还没有深入了解，因此需要合成修饰的类似物。这些修改也应该允许找到更有效的物种。该项目集中于通过修饰分子的一个结合位置来合成Salvinorin A的不同类似物。将与药理学家合作测试合成类似物的活性和结合模式。计算研究将完成这项工作。这个项目不仅将提供更深入的了解Salvinorin A及其类似物的结合模式。为该天然产物引入的新颖有效的合成策略也可应用于其他天然产物的制备。这里获得的知识将转移到类似的药物，有助于更合理的药物设计的强大的镇痛药。