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.
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.
|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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