Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation

R. D. Egleton, S. A. Mitchell, J. D. Huber, M. M. Palian, Robin L Polt, Thomas P Davis

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Abstract

Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser6 of a linear opioid peptide amide Tyr-D-Thr-Gly-Phe-Leu-Ser-NH2 on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 μg of peptide ligand. Glycosylation of Ser6 of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 ± 0.2 μl·min-1·g-1 to 2.2 ± 0.2 μl·min-1·g-1 (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain.

Original languageEnglish (US)
Pages (from-to)967-972
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number3
StatePublished - 2001

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Opioid Peptides
Blood-Brain Barrier
Glycosylation
Analgesia
Peptides
Brain
Biological Availability
Inbred ICR Mouse
Nervous System Diseases
Neuropeptides
Serum
Amides
Tail
Permeability
Central Nervous System
Perfusion
High Pressure Liquid Chromatography
Ligands
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. / Egleton, R. D.; Mitchell, S. A.; Huber, J. D.; Palian, M. M.; Polt, Robin L; Davis, Thomas P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 299, No. 3, 2001, p. 967-972.

Research output: Contribution to journalArticle

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