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.
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