Determining Structure-Activity Relationships through Synthesis and Assessment of Kappa Opioid Receptor Analogs for the Development of Potent, Biased Opioid Analgesics

Opioids, though commonly used for pain relief, cause harmful symptoms such as respiratory depression, constipation, and physical dependence. This occurs because the mu opioid receptor can recruit βarrestins—leading to the adverse symptoms mentioned previously—while also signaling via the G protein pathway, which is responsible for analgesia. The kappa opioid receptor (KOR) produces analgesia through G protein signaling, but leads to dysphoria and sedation upon βarrestin recruitment. Designing a biased ligand at the KOR that will signal primarily through the G protein pathway could lead to safer analgesic therapeutics. In past years, a new KOR agonist series modeled after lead compound ML 139 has been discovered. Data from previous structure–activity relationship (SAR) studies have determined distinct functional components of bisamide analogs that increase the relative potency of the scaffold. This project focuses on further modifications to identify structural features that may favor signaling through the G protein pathway. The results of these SAR studies are used to synthesize hybrid bisamide KOR agonists containing the most potent moieties. Additionally, another analog library, termed “fraggles,” with potential to yield KOR agonists with noteworthy potency and G protein bias is proposed.Bachelor of Scienc