The major goals of the Synthetic Core Facility, which was renovated by the University of Arizona specifically for this Program Project Grant are to synthesize, purify and perform necessary analytical work on 75 mg to 10 g quantities of bioactive peptides, novel amino acids and peptide mimetics that are needed for the extensive biochemical, pharmacological, biophysical and biological studies which are part of this Program Project Grant. Of specific importance will be the development of proper asymmetric synthetic methodology, other synthetic methods, purification methods and analytical methods that are needed for the various research projects and protocols.
The Specific Aims are: 1) To develop and establish all necessary synthetic methodologies, purification protocols, and analytical procedures that are needed for preparing any ligands that are needed by investigators in the Program Project Grant;2) To prepare 0.20 g to 2 g of biphalin, novel dynorphin A fragments, novel bivalent ligands that are agonists at opioid receptors and antagonists at bradykinin and other CNS receptors for extensive in vitro and in vivo biological activity studies and for biophysical studies;3) To prepare by asymmetric synthesis quantities (1 g to 10 g) of novel amino acids and peptide mimetics that are needed for the preparation of ligands for the Program Project;4) To prepare up to gram quantities of potent bioactive peptides, glycopeptides, peptidomimetics, and peptide conjugates that will be needed for biological and/or biophysical studies;and 5) To prepare any other peptides, peptide mimetics or other ligands that are needed by investigators in this Program Project Grant for further biological and biophysical studies.

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 #
8446519
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
$157,430
Indirect Cost
$53,516
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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