Design and Synthesis of Cyclic Arodyn Analogues by Ring-Closing Metathesis (RCM) for Kappa Opioid Receptor (KOP) Antagonists

Abstract

Introduction Our laboratory is interested in the design and synthesis of antagonists for kappa opioid receptor (KOP). In addition to their use as pharmacological tools, KOP antagonists have the potential to be used therapeutically in the treatment of cocaine and opioid dependence and also have antidepressant activity. Arodyn (Ac[Phe,Arg,D-Ala]Dyn A(1-11)NH2, Fig. 1) is an acetylated dynorphin A (Dyn A) analogue identified in our laboratory that is a potent and highly selective KOP antagonist. As a linear peptide, arodyn is very flexible and can adopt numerous conformations and is susceptible to metabolic degradation by peptidases. Therefore we are interested in the design and synthesis of cyclic arodyn analogues to restrict its conformation in order to study its possible bioactive conformation at KOP and to enhance the metabolic stability of the peptide. Ring-closing metathesis (RCM) has emerged as a very useful method of making cyclic organic compounds as well as cyclic peptides. Compared with the traditional approach of preparing cyclic peptides by disulfide or amide bond formation between amino acid side chains, cyclization by RCM has some advantages. The carbon-carbon bond is more stable than disulfide or amide bonds, and it is possible to maintain side chain functionalities when using RCM. Here we report the design and synthesis of cyclic arodyn analogues using RCM.