Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers - Project summary/abstract New medicines that effectively and safely treat chronic pain are desperately needed, as it is estimated that nearly 20% of the global population actively struggles with this debilitating disease. Opioids, the current standard of care for the treatment of moderate to severe pain, have significant side effects that include respiratory depression and addictive properties, and there are barriers to their equitable use around the globe. In the search for alternatives to opioid analgesics, sigma-1 (σ1R) and sigma-2 (σ2R) receptors are intriguing targets for drug development. σ1R and σ2R ligands can produce analgesia directly, can modulate mu opioid receptor-mediated analgesia, and may be particularly useful for neuropathic pain. Arthropod defensive secretions have been a source of potential new analgesics, with metabolites targeting a variety of neuroreceptors. Chemical investigations into millipedes, a diverse class (Diplopoda) of arthropods, reveal that millipedes produce structurally distinct defensive agents, including heterocyclic terpenoid alkaloids, oxidized aromatics, and cyanide-containing metabolites. Heterocyclic terpenoid alkaloids, produced by a single subterclass (Colobognatha), are structurally the most intriguing defensive secretions but the least studied. Recently, our group discovered ischnocybine A and demonstrated that it is a potent antagonist of the σ1R (Ki = 13.6 nM) with 100-fold selectivity over the σ2R (Ki = 1,292 nM). Initial ADME evaluations of ischnocybine A and a synthetic analog confirmed they possess promising central nervous system (CNS) properties, with good microsomal stability (t1/2 >255 min for analog) and permeability. Antagonists of both σRs have been implicated in the treatment of chronic pain, with several agents currently being evaluated in clinical trials for the treatment of neuropathic pain. Our research team includes natural product chemists, synthetic chemists, and pharmacologists with expertise in pain models at Virginia Tech (VT), University of California at Davis (UCD), and Rowan University, aim to leverage the defensive secretions from millipedes for the development of a new class of analgesics that may have less perceived detrimental effects. This research proposal aims to leverage millipede defensive secretions to treat chronic pain using chemical and biochemical techniques. Our work includes: Establishing preliminary structure-activity relationship (SAR) of ischnocybine A by incorporating natural functionality through semi-synthesis; asymmetric total synthesis of four millipede-derived alkaloids; and pharmacological evaluation of synthetic millipede alkaloids and analogs. Completion of the proposed work will elucidate a preliminary SAR of ischnocybine alkaloids, validate a short synthetic plan to access the natural alkaloid, and confirm that these lipophilic alkaloids can enter the CNS and modulate pain behaviors, thereby paving the way for subsequent detailed studies toward developing a new generation of analgesics.
