Synthesis of Natural Product-Based Probes for the Central Nervous System

Abstract

The number of individuals affected by a central nervous system disorder continues to steadily increase. Unfortunately, in many cases the available therapeutic options leaves these diseases undertreated and additional molecular probes are needed to fully understand these conditions. Historically, natural products have served as a rich source of new molecular scaffolds for developing these probes due to their complex structures and unique ability to perturb biological pathways through diverse mechanisms. With this in mind, the kappa opioid receptor (KOR) agonist salvinorin A, the mu opioid receptor (MOR) agonist herkinorin, and the anti-tau diarylheptanoid myricanol were identified as potential probes for investigating substance abuse, pain, and Alzheimer’s Disease, respectively. To determine how the unique neoclerodane structure of salvinorin A interacts with the KOR, methods to chemical modify the steric and electronic properties of the furan ring were developed. The resulting structure-activity relationships (SAR) identified three compounds that successfully attenuated drug seeking behavior in an animal model of drug relapse. In a separate study, a simple modification to the A-ring of herkinorin was found to drastically increase the potency and selectivity for the MOR, thus increasing the potential in vivo utility of the probe. Additional SAR studies also resulted in the first sub-nanomolar diterpene MOR agonist. Finally, an enantioselective route to both enantiomers of myricanol was developed to provide the necessary material for more extensive biological investigations into the compound’s tau degradation mechanism. The three studies described herein, highlight the importance of using chemical synthesis to modify and build complex natural products scaffolds in order to probe biological systems.