The long term goals of this research are to discover and design novel peptide and peptidomimetic ligands including bivalent ligands that can act as potent analgesics in chronic pain states (e.g. neuropathic pain, etc.) using new mechanisms of action, and that do not have the basic toxic side effects of current opioids such as respiratory depression and tolerance. For this purpose we are developing a comprehensive approach that includes computer assisted design of novel ligands;asymmetric synthesis of novel amino acids and p-turn mimetics;peptides and peptidomimetics with unique conformational and topographical properties;peptide ligands with unique biological properties;and use of a variety of biophysical studies of the conformational, topographical and dynamic properties of these ligands to help understand their unique biological properties and provide insights for further design. To pursue these goals we have the following Specific Aims: 1) To determine the structural features of non-opioid dynorphin A fragment peptides that may have interactions with a putative novel site of the bradykinin 2 receptor and activate it for a novel signaling pathway, and to develop antagonists for this novel binding site;2) To design and develop bivalent ligands in a single structure that act as mu/delta opioid agonists and bradykinin receptor antagonists, to obtain ligands that can treat neuropathic pain states with minimal side effects of opiates;3) To optimize structures of biphalin-related compounds that have mu/delta opioid activity but show minimal or none of undesirable toxic side effects of opioid ligands such as tolerance, and withdrawal symptoms;4) To explore the design and synthesis of novel constrained amino acids, amino acid chimeras, and p-turn mimetics that can bias side chain groups at x1 and x2 torsional angles and/or in preferred backbone conformations for incorporation into novel ligands to enhance in vitro and in vivo biological properties;5) To utilize computational and modeling methods and a number of biophysical tools including 2D NMR, CD, and plasmon waveguide resonance (PWR) spectroscopy to obtain novel insights into the relationships of conformational and topographical structure to biological activity, and to obtain insights into signal transduction by our novel ligands.

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 mechanism of pain control with minimal side effects, drug seeking behavior and tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA006284-22
Application #
8446521
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
22
Fiscal Year
2013
Total Cost
$189,957
Indirect Cost
$64,572
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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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