While narcotic analgesics such as morphine are important drugs for the treatment of severe pain, their use is limited because of serious side effects such as tolerance, respiratory depression, and the potential for drug abuse. Thus there is considerable interest in identifying analgesics with reduced liabilities for clinical use. Kappa opioid receptor (KOPr) ligands have shown therapeutic value in the treatment of pain, and potential for the treatment of mood disorders and drug abuse as well. Therefore exploring the structural requirements for KOPr activity is important to developing KOPr ligands as potential new medications. The proposed research focuses on peptide ligands for KOPr, which have not been studied as extensively as peptides for other opioid receptors. Recent studies in our laboratories have successfully identified a number of KOPr peptide ligands with unique pharmacological profiles that offer distinct advantages over current KOPr ligands, including some with potent antinociceptive activity in vivo. Therefore the goals of the proposed research in this competitive renewal application are to continue our structural studies of key peptidic ligands with activity at KOPr and to expand these studies to include evaluating peptides for opioid activity in vivo. The long term objectives of this research are to explore the structure-activity relationships (SAR) of peptide ligands with KOPr activity and to identify peptidic KOPr ligands with desirable pharmacological profiles for use in vivo.
Three specific aims will be pursued to accomplish these goals: 1) To explore the SAR of novel analogs of the dynorphins, the endogenous ligands for KOPr, 2) to explore the SAR of novel KOPr peptides that are structurally unrelated to the dynorphins, and 3) to evaluate peptide KOPr ligands in vivo using mouse models of analgesia, antinociceptive tolerance, physiological responses and place conditioning. We hypothesize that peptide agonists with mixed agonist/KOPr antagonist activity will demonstrate significant antinociception with decreased liabilities. The insights from these studies will further enhance our understanding of the roles of KOPr in various pharmacological processes and advance the development of KOPr ligands with potential for therapeutic application.

Public Health Relevance

While narcotic analgesics such as morphine have been used extensively to treat pain, their use has been limited by their serious side effects. Thus there is a need to identify promising lead compounds with improved side effect profiles that could result in improved treatment of pain. Compounds with mixed activity involving kappa opioid receptors may possess analgesic activity with fewer side effects, but the development of these mixed activity drugs has been limited. Antagonists blocking kappa opioid receptors may also have potential in the treatment of mood disorders and drug abuse. There is a clinical need for these agents, as described in this proposal that can be used as pharmacological tools and as lead compounds for further development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018832-08
Application #
8610907
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Hillery, Paul
Project Start
2005-02-15
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$284,991
Indirect Cost
$42,556
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Aldrich, J V; Senadheera, S N; Ross, N C et al. (2014) Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour. Br J Pharmacol 171:3212-22
Dimattio, K M; Yakovleva, T V; Aldrich, J V et al. (2014) Zyklophin, a short-acting kappa opioid antagonist, induces scratching in mice. Neurosci Lett 563:155-9
Ross, Nicolette C; Reilley, Kate J; Murray, Thomas F et al. (2012) Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting ? opioid receptor antagonism. Br J Pharmacol 165:1097-108
Aldrich, Jane V; Kulkarni, Santosh S; Senadheera, Sanjeewa N et al. (2011) Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208. ChemMedChem 6:1739-45
Fang, Wei-Jie; Yakovleva, Tatyana; Aldrich, Jane V (2011) A convenient approach to synthesizing peptide C-terminal N-alkyl amides. Biopolymers 96:715-22
Fang, Wei-Jie; Bennett, Marco A; Aldrich, Jane V (2011) Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 1: effects of cleavage conditions and N-terminal functionality. Biopolymers 96:97-102
Fang, Wei-Jie; Bennett, Marco A; Murray, Thomas F et al. (2011) Deletion of Ac-NMePhe(1) from [NMePhe(1) ]arodyn under acidic conditions, part 2: effects of substitutions on pharmacological activity. Biopolymers 96:103-10
Kulkarni, Santosh S; Ross, Nicolette C; McLaughlin, Jay P et al. (2009) Synthesis of cyclic tetrapeptide CJ 15,208: a novel kappa opioid receptor antagonist. Adv Exp Med Biol 611:269-70
Patkar, Kshitij A; Murray, Thomas F; Aldrich, Jane V (2009) The effects of C-terminal modifications on the opioid activity of [N-benzylTyr(1)]dynorphin A-(1-11) analogues. J Med Chem 52:6814-21
Fang, Wei-Jie; Cui, Yanjun; Murray, Thomas F et al. (2009) Design, synthesis, and pharmacological activities of dynorphin A analogues cyclized by ring-closing metathesis. J Med Chem 52:5619-25

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