Novel treatments for chronic pain with diminished risk of addiction have not been forthcoming despite much effort. Indeed there is increasing evidence that current treatment modalities themselves actually can exacerbate pain states. Recent studies in our laboratories and other laboratories suggest that new approaches are needed to deal with the changes in expressed genes that may underlie hyperalgesic actions, tolerance and negative reinforcement which may lead to drug seeking behavior. Thus there is a need for new kinds of treatment that require new approaches to drug design. To overcome these deficiencies and more fully understand new mechanisms that can explain why current methods for treating many chronic pain states (chronic inflammatory pain, neuropathic pain, visceral pain, etc.) are not successful, we will develop novel ligands based on new mechanistic insights that can overcome the undesirable actions of currently used opiates.
Our specific aims for this Program Project are: 1) Effective administration of the financial, personnel and scientific aspects of a highly multidisciplinary group of scientists in several departments;2) Operate an efficient and effective Synthesis Core to synthesize all the compounds needed in this project;3) Provide a multifacited Biochemical Core to perform as necessary binding affinity, second messenger, tissue and animal assays to advance this research;4) Design and synthesis of novel balanced mu/delta ligands that possess greatly reduced opioid toxicity and which show minimal or no tolerance;5) Design and synthesis of novel dynorphin A non-opioid ligands that act at a putative novel binding site on bradykinin receptors;6) Synthesize bivalent novel ligands that are mu/delta receptor agonists/bradykinin receptor antagonists that modulate pain;7)Develop novel pharmacology and molecular biology methods to provide an understanding of the mechanism(s) of action of non-opioid dynorphin ligands that affect bradykinin receptors and modulate chronic pain by novel pathways;8)Examine mechanisms of opioid induced neuroplasticity, opioid withdrawal and tolerance;9)Determine changes occurring in the CNS which lead to enhanced spinal levels of non-opioid dynorphins which interact with the bradykinin receptor to produce hyperalgesia and mediate opioid withdrawal and contribute to negative reinforcement and dependence;10) Determine the functional regulation of opioid receptors, especially as related to opioid induced tolerance/hypersensitivity.

Public Health Relevance

There are still many unmet public health needs in the treatment of pain and drug abuse in our society and worldwide. In this research we will examine the design, synthesis, and biological evaluation of novel peptide and peptidomimetic ligands for the treatment of prolonged pain, especially neuropathic pain that will address new mechanisms of pain control with minimal side effects such as drug seeking behavior and tolerance.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Human Development Research Subcommittee (NIDA)
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Hillery, Paul
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University of Arizona
Schools of Arts and Sciences
United States
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Lee, Yeon Sun; Muthu, Dhanasekaran; Hall, Sara M et al. (2014) Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord. J Am Chem Soc 136:6608-16
Meske, Diana S; Xie, Jennifer Y; Oyarzo, Janice et al. (2014) Opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain. Neurosci Lett 562:91-6
Lee, Yeon Sun; Rankin, David; Hall, Sara M et al. (2014) Structure-activity relationships of non-opioid [des-Arg(7)]-dynorphin A analogues for bradykinin receptors. Bioorg Med Chem Lett 24:4976-9
Vardanyan, Ruben S; Hruby, Victor J (2014) Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med Chem 6:385-412
Hruby, Victor J (2013) Adventures in peptides and science with students! the joys of research. Biopolymers 100:127-31
Nair, Padma; Yamamoto, Takashi; Largent-Milnes, Tally M et al. (2013) Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities. Bioorg Med Chem Lett 23:4975-8
Largent-Milnes, T M; Brookshire, S W; Skinner Jr, D P et al. (2013) Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects. J Pharmacol Exp Ther 347:7-19
Cai, Minying; Stankova, Magda; Muthu, Dhanasekaran et al. (2013) An unusual conformation of ýý-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells. Biochemistry 52:752-64
Petrov, Ravil R; Lee, Yeon Sun; Vardanyan, Ruben S et al. (2013) Effect of anchoring 4-anilidopiperidines to opioid peptides. Bioorg Med Chem Lett 23:3434-7
Liu, Zhihua; Mehta, Sukeshi J; Lee, Kwang-Soo et al. (2012) Thio-Claisen rearrangement used in preparing anti-ýý-functionalized ýý,ýý-unsaturated amino acids: scope and limitations. J Org Chem 77:1289-300

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