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

阿片类药物是一类众所周知的具有精神活性的天然、半合成或合成化合物，具有止痛和镇静特性。最受欢迎的自然遇到的阿片类药物是吗啡，它表现出极高的活性，但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。事实证明，当处理两类阿片受体时，就会对这些药物产生强烈的成瘾。Salvinorin A是一种自然产生的化合物，具有精神活性，可以在不导致成瘾的情况下缓解疼痛，因为它只刺激第三类阿片受体。用不同的方法研究和阐明了阿片受体的结构和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不是很清楚，因此需要合成修饰的类似物。这些修改还应该允许发现更多有效的物种。本项目致力于通过修饰分子的一个结合位置来合成不同的丹参素A类似物。合成的类似物的活性和结合模式将与药理学家合作进行测试。计算研究将完成这项工作。该项目不仅将提供对Salvinorin A及其类似物结合模式的更深层次的了解。为该天然产物引入的新颖和高效的合成策略也可应用于其他天然产品的制备。这里所获得的知识将被转移到类似的药物中，为更合理的强效止痛药的药物设计做出贡献。

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.