Because of the serious side effects associated with mu opioid analgesics such as morphine there is considerable interest in developing ligands for other opioid receptor types as both pharmacological tools and potential therapeutic agents. Kappa (k) opioid receptors are involved in a variety of physiological and pharmacological effects, including peripheral as well as centrally mediated analgesia. Drug abuse, particularly opioid and cocaine abuse, is a major problem, resulting in consequences for both the individual and society. Kappa receptor agonists and antagonists may find utility in the treatment of cocaine and opioid abuse, respectively. Kappa receptor ligands also have a number of other potential therapeutic applications, including as neuroprotective agents and potentially in the treatment of AIDS. The interactions of ligands, particularly peptides, with Kappa opioid receptors appear to be more complex than the interactions of ligands with mu or delta opioid receptors. Therefore the long-term objectives of this research are to examine novel peptidic ligands with high kappa opioid receptor affinity and selectivity that can be used as pharmacological tools to better understand Kappa receptor-peptide interactions at a molecular level. This proposal uses a combination of approaches (synthesis, conformational analysis, and pharmacological evaluation) and an iterative strategy to explore structure-activity relationships (SAR) and develop pharmacophoric models for the interactions of peptide ligands, both agonists and antagonists, with kappa receptors. This research has three specific aims: 1) to explore the SAR of the N-terminal sequences of dynorphin A analogs;2) to explore modifications in the C-terminal sequence of these peptides to understand the roles of basic residues in different peptide ligands for Kappa receptor interaction, and 3) to study novel small peptides unrelated to dynorphin A that have high kappa receptor affinity. In addition to identifying important pharmacological tools that can be used to study Kappa opioid receptors, this research should significantly advance our understanding of how peptide ligands interact with these receptors. These insights will be complimentary to those found for non-peptide ligands and could be very important in the development of new kappa receptor ligands, including agents with potential therapeutic benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018832-05
Application #
7563238
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2005-02-15
Project End
2011-02-14
Budget Start
2009-02-15
Budget End
2011-02-14
Support Year
5
Fiscal Year
2009
Total Cost
$341,116
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Fang, Wei-Jie; Murray, Thomas F; Aldrich, Jane V (2018) Design, synthesis, and opioid activity of arodyn analogs cyclized by ring-closing metathesis involving Tyr(allyl). Bioorg Med Chem 26:1157-1161
Joshi, Anand A; Murray, Thomas F; Aldrich, Jane V (2017) Alanine scan of the opioid peptide dynorphin B amide. Biopolymers 108:
Huang, Peng; Yakovleva, Tatyana; Aldrich, Jane V et al. (2016) Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests. Neurosci Lett 615:15-20
Joshi, Anand A; Murray, Thomas F; Aldrich, Jane V (2015) Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin. J Med Chem 58:8783-95
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
Aldrich, Jane V; McLaughlin, Jay P (2012) Opioid Peptides: Potential for Drug Development. Drug Discov Today Technol 9:e23-e31
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
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
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

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