Improved bioavailability to the brain of glycosylated Met-enkephalin analogs

The blood-brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodol ogy for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cy clic opioid peptide [D-Cys(2.5),Ser(6),Gly(7)] enkephalin. The peptide was glycosylated on the Ser(6) via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, phys iochemical attributes, in situ brain uptake in female Sprague-Dawley rats a nd antinociception in male ICR mice. Glycosylation resulted in a slight dec rease in affinity to the delta -opioid receptor, and mixed effect on bindin g to the mu -opioid receptor. There was a significant decrease in lipophili city resulting from glycosylation and a slight reduction in binding to bovi ne serum albumin. In situ perfusion showed that brain uptake was improved b y up to 98% for several of the glycosylated peptides, and the nociceptive p rofiles of the peptides, in general, followed the rank order of peptide ent ry to the brain with up to a 39-fold increase in A.U.C. (C) 2000 Elsevier S cience B.V. All rights reserved.