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

• Applicant: Dr. Lucilla Levi
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: Funded in 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 355558520

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Craig Forsyth