Glycopeptide enkephalin analogs: Design, synthesis, biophysical and pharmacological evaluation of potent analgesics with reduced side-effects

Abstract

Pain relief is one of the most fundamental, yet elusive goals of medicine. In the mammalian brain, one means of pain suppression is through activation of the opioid receptors. The opioids themselves are a broad class of centrally acting ligands that may target the delta, kappa, and/or mu opioid receptors in the brain or the spinal column in order to produce pain relief. Glycopeptides have been shown to be versatile, non-toxic alternatives to morphine-induced analgesia in mice. In order to further explore the limits of glycopeptide analgesics, we have synthesized three series of glycopeptide enkephalin analogues (linear glycopeptides, lipo-glycopeptides, and amphipathic alpha-helical glycopeptides) in order to explore the pharmacology and glycopeptide-membrane interactions associated with high-affinity receptor agonism. The three classes of compounds were designed to interact with the cellular membrane to a different degree, and in varying modes of action. Each class of compounds has presented different challenges, but display diverse in vitro and in vivo profiles. Overall, the glycopeptides have shown excellent potential as advanced drug candidates. Total synthesis, circular dichroism, 2-D NMR, molecular modeling, membrane interaction, in vitro binding, in vivo analgesia and dependence liability studies have been performed and will be discussed.