Design and Synthesis of Novel Linear and Cyclic Peptide Ligands for Kappa Opioid Receptors

Our research focuses on the development of potent and highly selective peptide ligands for kappa (κ) opioid receptors and examination of the structure-activity relationships (SAR) for activity at these receptors. Both κ opioid receptor agonists and antagonists have potential therapeutic applications for a variety of diseases. Dynorphin (Dyn) A is an endogenous heptadecapeptide agonist at κ opioid receptors. Dyn A-based peptide antagonists could be useful pharmacological tools for studying κ opioid receptors. Arodyn is an acetylated Dyn A analog identified in our laboratory that is a potent and highly selective κ opioid receptor antagonist. One main purpose of this dissertation research was to evaluate the role of the N-terminal 'message' sequence (especially Phe1 and Phe3) of arodyn in κ opioid receptor affinity, selectivity and efficacy. These two positions were substituted with other aromatic or nonaromatic residues. The other main purpose of this research was to develop conformationally restricted analogs of arodyn and Dyn A with high affinity and/or selectivity that can be used to explore the structural and conformational requirements for interaction of these ligands with κ opioid receptors, and to explore the SAR for agonist vs. antagonist activity at κ receptors. Different cyclization strategies were explored for the synthesis of cyclic arodyn and Dyn A analogs, including cyclization through lactam bond formation or ring-closing metathesis (RCM)