Glycosyl-Enkephalins: Synthesis and Binding at the Mu, Delta & Kappa Opioid Receptors. Antinociception in Mice
Opioid peptides are unstable toward enzymatic biodegradation, resulting in poor bioavailability in tissues and organs, and hence are not effective analgesic agents. Glycosylation of small peptides increases the hydrophilicity, stability, and bioavailability of peptides and hence transport across the blood-brain barrier (BBB) [1, 2, 3]. BBB penetration studies of glycopeptides have indicated up to a 3-fold increase in the rate of brain delivery of these compounds compared with the unglycosylated parent peptides [4,5]. Also glycosylation of the naturally occurring μ-selective dermophin and δ-selective deltorphin opioid agonists resulted in analogues with higher brain permeability and greater analgesic actions [6,7]. Therefore, glycosylation seems to be an ideal strategy for the development of drug candidates for analgesia.
The carbohydrate moiety plays important roles in both the mechanism of transport of glycosylated peptides across the BBB, as well as stability towards...
KeywordsCarbohydrate Moiety Kappa Opioid Receptor Automate Solid Phase Hydrophilic Side Chain MBHA Resin
We thank the Office of Naval Research (N00014-05-1-0807 & N00014-02-1-0471) and the National Science Foundation (CHE-607917) for support of these studies.