The design and synthesis of imine-bridged cyclic peptides andthe solid phase synthesis of β-turn mimetics

Abstract

Pain is perhaps the most unpleasant sensation humans experience. While pain is important in preventing further injury and as a detection mechanism for ill-health; effective relief of pain, especially chronic or neuropathic, is a critical quality of life issue. As discoveries are made regarding opioid receptor-acceptor-ligand interactions, ligands that bind specifically to a receptor subtype can modify behavior without triggering side effects. Topographical space control is an important consideration in ligand design. According to Ramachandran¹, α-amino acids are confined to the following low-energy conformations, α-helix, β-sheets, extended structures, and β-turns. Endogenous peptides such as the enkephalins and endomorphins activate the opioid receptor subtypes, δ- and μ-, respectively, and are involved in the pain cascade. Research herein concerns the synthesis of δ-opioid peptidomimetics that replace the Gly-Gly unit of Leu-enkephalins with a β-turn mimetic moiety. Additionally, using the bioactive nostocyclopeptolides as templates, smaller cyclized imino-bridged peptides were designed. These peptides were developed with the mu-opioid subtype requirements in mind.