Kevin Tidgewell

Mentor: Thomas E. Prisinzano, PhD

Year Entered Into Program: 2003

PhD Institution: University of Iowa, 2007

Affiliations

  • Medicinal and Natural Products Chemistry

Research Description

The Prisinzano Lab investigates the interactions of drugs with the central nervous system (CNS). Through the elucidation of the mechanism of action of these drugs, we can begin to more clearly understand the underlying mechanism of addiction as well as begin to develop novel therapeutics for its treatment. In particular, we are very interested in the mechanism and modulation of neuropathic and chronic pain. In order to understand the mechanism of pain transmission and the pathways involved, selective agonists and antagonists are required for receptors involved in these pathways. Many pharmacological tools have come from natural sources and so the investigation of a novel natural source for opioid ligands provides a unique source for the development of new pharmacological treatments for pain. My research focuses on the novel kappa opioid ligand salvinorin A isolated from the Mexican sage Salvia divinorum. By systematically modifying salvinorin A, we will generate a better understanding of the required pharmacophore for affinity and activity at opioid receptors. Additionally, compounds which show promise (i.e. high selectivity and affinity) will be tested in in vivo pharmacological tests of nociception and drug self-administration. This plan of investigation will follow the complete process of drug discovery from isolation, to chemical synthesis and pharmacological testing in vivo. 

Award(s)

  • Recipient of National Medicinal Chemistry Symposium Travel Award, 2006
  • Recipient of AFPE Pre-Doctoral Fellowship, 2005-2007

Publications

  1. Prisinzano, T., Podobinski, J., Tidgewell, K., Luo, M., Swenson, D.:  Synthesis and Determination of the Absolute Configuration of the Enantiomers of Modafinil. Tetrahedron-Asymmetr. 15:1053-1058, 2004.
  2. Tidgewell, K., Harding, W.W., Schmidt, M., Holden, K.G., Murry, D.J., Prisinzano, T.E.:  A Facile Method for the Preparation of Deuterium Labeled Salvinorin A: Synthesis of [2,2,2-2H3]-Salvinorin A, Bio. Med. Chem. Letters. 2004 (14):5099-5102, 2004.  PMID: 15380207
  3. Schmidt, M.S., Prisinzano, T.E., Tidgewell, K., Harding, W., Butelman, E.R., Kreek, M.J., Murry, D.J.:  Determination of Salvinorin A in Body Fluids by LC-MS/APCI  J. Chromatog. B. 818:221-225, 2005.  PMID: 15734162
  4. Harding, W.W., Tidgewell, K., Schmidt, M., Shah, K., Dersch, C.M., Snyder, J., Parrish, D., Deschamps, J.R., Rothman, R.B., Prisinzano, T.E.:  Salvinicins A and B, New Neoclerodane Diterpenes from Salvia divinorum. Org. Lett.  7:3017-3020, 2005. PMCID: PMC2535573
  5. Harding, W.W., Tidgewell, K., Byrd, N., Cobb, H., Dersch, C.M., Butelman, E.R., Rothman, R.B., Prisinzano, T.E.:  Neoclerodane Diterpenes as a Novel Scaffold for m Opioid Receptor Ligands. J. Med. Chem. 48:4765-4771, 2005. PMID: 16033256
  6. Prisinzano, T.E., Tidgewell, K., Harding, W.W.:  k Opioid Ligands as Treatment for Stimulant Dependence. AAPS. J. 7:E592-599, 2005. PMCID: PMC2751263
  7. Schmidt, M.D., Schmidt, M.S., Butelman, E.R., Harding, W.W., Tidgewell, K.J., Murry, D.J., Kreek, M.J., Prisinzano, T.E.:  Pharmacokinetics of the Plant-Derived kappa opioid Hallucinogen Salvinorin A in Nonhuman Primates. Synapse 58:208-210, 2005. PMID: 16138318
  8. Harding, W.W., Schmidt, M., Tidgewell, K., Kannan, P., Holden, K.G., Gilmour, B., Navarro, H., Rothman, R.B., Prisinzano, T.E.:  Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Semisynthesis of Salvinicins A and B and Other Chemical Transformations of Salvinorin A. J. Nat. Prod. 69:107-112, 2006. PMCID: PMC2544632
  9. Harding, W.W., Schmidt, M.D., Tidgewell, K., Kannan, P., Holden, K.G., Dersch, C.M., Rothman, R.B., Prisinzano, T.E.:  Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Selective Modification of the Furan Ring. Bio. Med. Chem. Letters.  16:3170-3174, 2006. PMID: 16621556
  10. Tidgewell, K., Harding, W.W., Lozama, A., Cobb, H., Shah, K., Kannan, P., Dersch, C.M., Parrish, D., Deschamps, J.R., Rothman, R.B., Prisinzano, T.E.:  Synthesis of Salvinorin A Analogues as Opioid Receptor Probes. J.Nat.Prod. 69:914-918, 2006. PMID: 16792410
  11. Xu, H., Partilla, J. A., Wang, X., Rutherford, J.M., Tidgewell, K., Prisinzano, T.E., Bohn, L.M., Rothman, R.B.:  A Comparison of Non-Internalizing (Herkinorin) and Internalizing (Damgo) Mu Opioid Agonists on Cellular Markers Related to Opioid Tolerance and Dependence. Synapse. 61(3):166-175, 2007.  PMID: 17152090
  12. Butelman, E.R., Mandau, M., Tidgewell, K.,  Prisinzano, T.E., Yuferov, V., Kreek, M.J.:  Effects of salvinorin A, a -opioid hallucinogen, on a neuroendocrine biomarker assay in non-human primates with high -receptor homology to humans. J. Pharm. Exp. Ther. 320(1):300-306, 2007. PMID: 17060493
  13. Groer, C.E., Tidgewell, K., Moyer, R.A., Harding, W.W., Rothman, R.B., Prisinzano, T.E., Bohn, L.M.:  An Opioid Agonist that Does Not Induce Mu Opioid Receptor – Arrestin Interactions or Receptor Internalization. Mol Pharm. (71):549-557, 2007. PMID: 17090705
  14. Rothman, R.B., Murphy, D.L., Xu, H., Godin, J.A., Dersch, C.M., Partilla, J.S., Tidgewell, K., Schmidt, M., Prisinzano, T.E.:  Salvinorin A: Allosteric Interactions at the Mu Opioid Receptor. J. Pharm. Exp. Ther. 320(2):801-810, 2007. PMID: 17060492
  15. Holden, K.G., Tidgewell, K., Marquam, A., Rothman, R.B., Navarro, H., Prisinzano, T.E.:  Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position. Bio. Med. Chem. Letters. (17):6111-6115, 2007. PMCID: PMC2111044
  16. Tidgewell, K., Groer, C.;,Harding, W.W., Lozama, A., Schmidt, M., Marquam, A., Hiemstra, J., Partilla, J.S., Dersch, C.M., Rothman, R.B., Bohn, L.M., Prisinzano, T.E.:  Herkinorin analogues with differential beta-arrestin-2 interactions. J. Med. Chem. 51(8):2421-2431, 2008. PMCID: PMC2494883

Award(s) since graduating from the U of IA

  • R15 AT008060-02, NIH/NCCIH “CNS Drug Discovery from the Ocean: Cyanobacterial Secondary Metabolites to Treat Comorbid Pain and Depression (Co-PI), 2018-present
  • R25 NS100118-01A1, NIH/NINDS “Pain and Neurodegenerative Undergraduate Research Experiences (PURE/NURE): Utilizing community partners to build specialized and enhanced neurological disease research programs for undergraduates (Co-PI), 2018-present
  • International Association for the Study of Pain. “Using ethnopharmacological knowledge from Cameroon to develop novel Sigma 2 receptor agonists for pain treatment.” (Co-PI), 2018-present
  • Loogman Faculty Research Grant, Center for African Studies. “A multi-continent collaboration in pain research and treatment: Using ethnopharmacological knowledge from Cameroon to develop novel pain treatments. (Co-PI), 2017-2018
  • R15 AT00800, NIH NCCAM “Cyanobacterial Natural Products to Treat Comorbid Pain and Depression.” (Co-PI), 2014-2018
  • American Society of Pharmacognosy Research Starter Grant. “Explorations of Honduran Marine Cyanobacteria for GPCR Ligands, (PI), 2013-2015
  • Duquesne Faculty Development Fund. “Investigation of Cyanobacterial Natural Products for Comorbid Pain and Depression, (Co-I), 2013-2015
  • American Pain Society Sharon S. Keller Award. “Cyanobacterial Natural Products to Treat Comorbid Pain and Depression, (Co-I), 2013-2016

Research