Development of Non-covalent Chemical Probes for μ, δ and κ Opioid Receptors

Abstract

Opioids are well-known pain relievers and one of several therapeutic options for pain management. Although opioids are very effective analgesics, continued use and abuse can lead to physical dependence and withdrawal symptoms. Their side effects, such as constipation, respiratory depression, and the development of tolerance, addiction liability and abuse, highlight the need for safer opioid prescribing practices. The development of new chemical probes will assist in further understanding opioid-receptor interactions and will serve to advance this field of research. As a part of a collaborative Ontario Tech University-Purdue Pharma program, the synthesis of opioid derivatives for use as chemical probes was undertaken to better understand the structure-activity relationships of opioid receptors. The initial efforts were focused on the preparation of an essential building block 1-bromocodeine. The bromination of codeine affords an attractive platform for further functionalization and the synthesis of other opioid derivatives. Here we describe the development of a new methodology for the large-scale bromination of codeine under mild conditions, which was applied for the preparation of a broad range of codeine derivatives. The developed protocol is safer and has a higher yield than the commonly employed procedure for the bromination of codeine, which involves toxic HBr gas. In addition, our efforts toward the synthesis of natural product Bismorphine A revealed that bismorphine and pseudomorphine have the same structure. Consequently, we successfully prepared a series of novel opioid derivatives, which appear to have a high affinity for MOR (Mu Opioid Receptor). The synthesis and biological activities of a series of opioid derivatives are reported.