Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers
NCCIH - National Center for Complementary and Integrative Health
About This Grant
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.
Grant Summary
Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers is a NCCIH - National Center for Complementary and Integrative Health grant providing up to $451K for university, nonprofit, healthcare org. Applications are due 2028-06-30 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $451K
2028-06-30
- 1Confirm your organization is eligible for Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers from NCCIH - National Center for Complementary and Integrative Health, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NCCIH - National Center for Complementary and Integrative Health before the deadline.
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Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers: Frequently Asked Questions
Who is eligible for the Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers?
Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers is offered by NCCIH - National Center for Complementary and Integrative Health and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers provide?
Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers provides up to $451K per award from NCCIH - National Center for Complementary and Integrative Health. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers deadline?
Applications for Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers are due 2028-06-30 (open). Because deadlines can change, verify the date with the funder, NCCIH - National Center for Complementary and Integrative Health, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers?
To apply for Discovery and Development of Millipede Alkaloids as a New Generation of Painkillers, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCCIH - National Center for Complementary and Integrative Health.