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.

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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University of Arizona
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Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano et al. (2018) Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors. Bioorg Med Chem 26:3664-3667
Mowlazadeh Haghighi, Saghar; Zhou, Yang; Dai, Jixun et al. (2018) Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation. Eur J Med Chem 151:815-823
Sandweiss, A J; McIntosh, M I; Moutal, A et al. (2018) Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential. Mol Psychiatry 23:1745-1755
Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita et al. (2017) Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158:2386-2395
Vardanyan, Ruben S; Cain, James P; Haghighi, Saghar Mowlazadeh et al. (2017) Synthesis and Investigation of Mixed ?-Opioid and ?-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain. J Heterocycl Chem 54:1228-1235
Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake et al. (2017) Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56:4201-4209
Remesic, Michael; Lee, Yeon Sun; Hruby, Victor J (2016) Cyclic Opioid Peptides. Curr Med Chem 23:1288-303
Ramos-Colon, Cyf N; Lee, Yeon Sun; Remesic, Michael et al. (2016) Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the ? Opioid Receptor. J Med Chem 59:10291-10298
Hall, Sara M; Lee, Yeon Sun; Hruby, Victor J (2016) Dynorphin A analogs for the treatment of chronic neuropathic pain. Future Med Chem 8:165-77
Deekonda, Srinivas; Cole, Jacob; Sunna, Sydney et al. (2016) Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations. Bioorg Med Chem Lett 26:222-7

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