Synthesis towards Salvinorin Scaffold to Develop a Potential Pain Therapeutic and Selective, Potent Kappa Opioid Ligands

Effective chronic pain management has posed a challenge for patients who have sought after traditional therapy, opioid analgesics. Particularly in patients with chronic pancreatitis, traditional therapy has failed to assist with pain management causing daily activity to be an even bigger challenge. Drugs like morphine or codeine, mu opioid agonists, have been utilized for pain management although these agonists have non-selective, opioid receptor subtype activity and side effects that ensue with chronic use that include constipation, addiction and respiratory depression. With the pancreas having a high density of kappa opioid receptors, a kappa subtype selective agonist could serve as a target molecule to develop as a pain therapeutic for patients with chronic pancreatitis. Where most alkaloids isolated over the years share characteristics like being plant derived, having similar structural functionalities and having cross affinity to opioid receptor subtypes, Salvinorin A has emerged as a very unique alkaloid. Salvinorin A is a non-nitrogenous alkaloid that selectively binds to the kappa opioid receptor subtype, implicating it as a potential target for development as a pain therapeutic for chronic pancreatitis as well as a scaffold for selective kappa opioid ligands. Synthesis of the Salvinorin scaffold is the basis of this body of work to not only build on the profile established in previous work but characterize through modifications that only synthesis can provide. This dissertation describes the synthesis of the key molecule as the pivotal molecule for generating analogues for the Salvinorin scaffold. Likewise, this work demonstrates the nociception response of Salvinorin A in the persistent pancreatitis model. Salvinorin A serves as a unique target for development both chemically and biologically; and this work establishes the foundation to bridge the gap between the two.