Treatment of pain remains a major unmet medical need. Opiate drugs continue to be the most important therapies for the treatment of moderate to severe pain but suffer from severe side effects that diminish quality of life. It is known that neurons in the pain transmission and modulatory pathways undergo plasticity that results in amplification of pain signaling in settings of tissue injury (i.e. the conditions in which pain relieving drugs are used). Unexpectedly, such pronociceptive adaptations also occur as a consequence of repeated exposure to opiates. Increased signaling through the substance P-NK1 pathway strongly contributes to peripheral and central sensitization to enhance pain. This multidisciplinary proposal involving five different laboratories, is aimed at testing the hypothesis that pain relieving drugs can be designed with a priori consideration of mechanisms of amplification that diminish desired analgesia, i.e., drug design for disease. We hypothesize that drugs that have opioid agonist (mostly mu) and NK-1 antagonist activity within a single molecule would provide effective pain relief, particularly in conditions of chronic pain with diminished side effects allowing for greater tolerability and increased quality of life. Thus, we propose to exploit recent developments in our de novo design and pain-related pharmacology, physiology and molecular biology to develop new classes of peptidomimetic ligands with a profile of mu/delta opioid receptor agonist activities and neurokinin 1 antagonist activities.
Our Specific Aims are:
Aim 1 : To design, synthesize and characterize novel metabolically stable and systemically active bifunctional ? preferring ?/4 opioid agonist ligands with NK-1 antagonist activities based on TY027, a current lead compound (delta opioid agonist preferring/NK1 antagonist). Biophysical studies (NMR, CD, PWR, etc.) in conjunction with computational chemistry will be used to evaluate 3-D conformations critical to bioactivity.
Aim 2 will characterize the pharmacology of these compounds in vitro and in vivo for (a) analgesic/antihyperalgesic efficacy;(b) propensity for developing antinociceptive tolerance and opioid-induced hyperalgesia;(c) sedation;(d) gastrointestinal side effects;and (f) addictive liability.
Aim 3 will evaluate the (a) metabolic stability of our novel compounds, (b) perform pharmacokinetic analysis, (c) evaluate BBB penetration and whether the compounds are substrates for P- glycoproteins, and (d) perform a broad screen for possible off-target activities. Our goal will be to discover a highly efficacious ligand, and backup ligand, that can be brought forward as a preclinical drug candidate during this grant period.

Public Health Relevance

This grant involving 5 principal investigators will develop a novel class of bioavailable ligands that can treat long term and neuropathic pain without the development of tolerance or drug seeking behavior These novel compounds will lack other undesirable side effects and toxicities of current drugs for treating pain. These compounds have mu/delta opioid agonist activities and neurokinin-1 antagonist activities providing a new approach to acute and chronic pain treatment. A clinical candidate will be identified during this grant period.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013449-14
Application #
8606202
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Hillery, Paul
Project Start
2000-09-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
14
Fiscal Year
2014
Total Cost
$509,990
Indirect Cost
$168,807
Name
University of Arizona
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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
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
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
Lee, Yeon Sun; Kupp, Robert; Remesic, Michael V et al. (2016) Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors. Chem Biol Drug Des 88:615-9
Bird, M F; Vardanyan, R S; Hruby, V J et al. (2015) Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands. Br J Anaesth 114:646-56
Nair, Padma; Yamamoto, Takashi; Cowell, Scott et al. (2015) Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities. Bioorg Med Chem Lett 25:3716-20
Mehr-un-Nisa; Munawar, Munawar A; Lee, Yeon Sun et al. (2015) Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs. Bioorg Med Chem 23:1251-9
Giri, Aswini Kumar; Apostol, Christopher R; Wang, Yue et al. (2015) Discovery of Novel Multifunctional Ligands with μ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain. J Med Chem 58:8573-83
Lee, Yeon Sun; Hall, Sara M; Ramos-Colon, Cyf et al. (2015) Blockade of non-opioid excitatory effects of spinal dynorphin A at bradykinin receptors. Receptors Clin Investig 2:

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