Unlocking the Therapeutic Potential of the Veratrum Alkaloids

Project Summary/Abstract Chronic pain is a debilitating condition suffered by a consistently large percentage of the global population. Current treatment options such as opioids suffer from undesired side effects, including high risk of addiction. Natural products have gained considerable attention from the pharmaceutical industry as non-opioid alternatives for treating pain, including neurotoxins such as tetrodotoxin and saxitoxin. These alkaloids work by blocking voltage-gated sodium channels, preventing the firing of action potentials and transmission of pain signaling. This represents a non-euphoric and non-addictive strategy for treating pain. One family of neurotoxic natural products that remain underexplored by the pharmaceutical industry are the Veratrum alkaloids. Veratrum, the genus of flowering plant these steroidal alkaloids are isolated from, has a long history of use in traditional Chinese medicine as an analgesic. Biological evaluation of its constituent natural products has been significantly hampered by low isolation yields from plant material, making laboratory synthesis the most reliable route to obtaining sufficient quantities of the compounds for thorough pharmacological evaluation. The proposed research project concerns the total synthesis of several Veratrum alkaloids that have thus far evaded laboratory preparation: the highly analgesic veratravine D and veratravine E and the partially-saturated D-ring congener hosukinidine (Aim 1). Each of the proposed syntheses utilizes common intermediates from the recently completed Trauner group total synthesis of veratramine and 20-epi-veratramine and features an intramolecular, transition-metal-catalyzed Diels–Alder reaction for the construction of the steroidal D-ring. The proposed research project also concerns the evaluation of the previously prepared veratramine and 20-epi- veratramine, along with the natural products prepared in Aim 1, across a variety of ion channels implicated in pain signaling to definitively establish their analgesic mechanism-of-action (Aim 2). This will primarily be accomplished by transfecting cells with the genes encoding the relevant channel and performing whole-cell patch clamp electrophysiology in the presence of the natural products. Targets that will be evaluated include Nav1.7, NaV1.8, CaV2.2, and TRPV1 channels. Molecular docking will be performed to rationalize the observed biological activities. The work will be completed in the University of Pennsylvania Department of Chemistry and Perelman School of Medicine, where the sponsor Prof. Dirk Trauner has joint appointments. The Trauner laboratory has extensive experience in both natural product total synthesis and neuropharmacology, with all of the relevant instrumentation and equipment to conduct research in either field. The project will allow the applicant to continue to refine his abilities in synthetic organic chemistry, as well as acquire new skills in patch clamp electrophysiology, cellular biology, and molecular docking.