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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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, R. Polt and T. P. Davis
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 967-972;
R. D. Egleton
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S. A. Mitchell
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J. D. Huber
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M. M. Palian
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R. Polt
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T. 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.

Footnotes

  • ↵1 Current address: Neurogen Corporation, Branford, CT 06405.

  • This work was supported by National Institutes of Health Grants DA 11271, DA 06284, and DA 06037.

  • Abbreviations:
    BBB
    blood-brain barrier
    BSA
    bovine serum albumin
    RAGE
    receptor for advanced glycation end products
    • Received July 12, 2001.
    • Accepted August 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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, R. Polt and T. P. Davis
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 967-972;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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, R. Polt and T. P. Davis
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 967-972;
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