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镇痛和镇静作用的天然、半合成或合成的精神活性化合物。最常见的天然阿片类药物是吗啡，它具有极高的活性，但具有引发强烈成瘾的严重副作用。在人体内，阿片的药理作用是由阿片受体介导的，主要分为三类。事实证明，当两类阿片受体被处理时，对这些药物的强烈成瘾就会出现。Salvinorin A是一种天然存在的化合物，具有精神活性特性，可以缓解疼痛，但不会导致成瘾，因为它只刺激第三类阿片受体。通过不同的方法对其结构、立体化学以及与阿片受体的结合方式进行了研究和澄清。然而，这种药物的确切作用尚不清楚，因此需要合成修饰的类似物。这些修改也将有助于发现更强效的物种。本项目主要通过修饰Salvinorin A分子的一个结合位置来合成多种Salvinorin A类似物。合成的类似物的活性和结合方式将与药理学家合作进行测试。计算研究将完成这项工作。该项目不仅对Salvinorin a及其类似物的结合模式有了更深入的了解。本研究为该天然产物的合成提供了新的、高效的合成策略，也可应用于其他天然产物的制备。在此获得的知识将转移到类似的药物，有助于更合理的强效镇痛药的药物设计。

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.