by the Chemistry Core. These compounds will be designed as opioid agonists and bradykinin/dynorphin antagonists in order to produce potent and efficacious antinociception targeting the pathology of neuropathic pain while eliminating antinocicpetive tolerance. The Biochemical Core contains 7 aims that will test such novel compounds. The in vitro pharmacological data in particular will provide timely feedback to the Chemistry Core on the structure-activity relationship (SAR) to further inform chemistry design. The initial binding and functional characterization of all novel compounds (est. 20 to 50 compounds/year) is necessary and essential for target-based drug discovery. To identify lead compounds, we must evaluate their affinity at multiple opioid and bradykinin receptors, and their apparent biological activity at each of these receptors. Studies will include in vitro tissue assaysto determine agonist and antagonist activity as well as novel compound activity at calcium channles using calcium fluorimetric analysis in transfectd cells. We will use a number of in vivo animal models to identify whether such novel bi-functional compounds produce antinociception as well as antihyperalgesia in inflammatory and chronic pain states. Finally, in vivo studies will be performed to detemine whether such compounds will result in antinocicpetive tolerance. Overall, Studies will be performed to identify molecules with agonist activity at one receptor and concurrent antagonist actions at a second receptor. The biochemical core provides dedicated equipment, personnel and expertise in data analysis for the entire project. It serves to centralize the use and maintenance of shared equipment and the technical training of personnel to use these equipment, management and oversight of animal protocols required by IACUC and Radiation Control, as well as to ensure data and information sharing with the Chemistry Core and the other projects. The biochemical core will synergize with projects A, C and D by providing lead compounds to directly test their hypotheses.

Public Health Relevance

(Seeinstructions): Inflammatory and chronic neuropathic pains are growing areas of unmet medical need. Clinically, chronic pain remains poorly controlled by available therapies and thus adversely impacts quality of life (Arner & Meyerson, 1988). One reason for this lack of effect is the absence of compounds that specifically target the pathology of neuropathic pain. The goal of the chemistry &biochemical core of this PPG are to synthesize and test compounds that result in potent and efficacious antinociception while eliminating tolerance. PROJECT/

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA006284-21
Application #
8378116
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
21
Fiscal Year
2012
Total Cost
$332,166
Indirect Cost
$112,915
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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
Sandweiss, A J; McIntosh, M I; Moutal, A et al. (2017) Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential. Mol Psychiatry :
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
Hall, Sara M; LeBaron, Lindsay; Ramos-Colon, Cyf et al. (2016) Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain. ACS Chem Neurosci 7:1746-1752
Deekonda, Srinivas; Rankin, David; Davis, Peg et al. (2016) Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands. Bioorg Med Chem 24:85-91
Lee, Yeon Sun; Remesic, Michael; Ramos-Colon, Cyf et al. (2016) Cyclic non-opioid dynorphin A analogues for the bradykinin receptors. Bioorg Med Chem Lett 26:5513-5516
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
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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