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Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

Author

Listed:
  • Md Tariqul Haque Tuhin

    (University of the Pacific)

  • Dengpan Liang

    (University of the Pacific)

  • Fang Liu

    (University of the Pacific)

  • Hala Aldawod

    (University of the Pacific)

  • Toufiq Ul Amin

    (University of the Pacific)

  • Joshua S. Ho

    (University of the Pacific)

  • Rasha Emara

    (University of the Pacific)

  • Arjun D. Patel

    (University of the Pacific)

  • Melanie A. Felmlee

    (University of the Pacific)

  • Miki S. Park

    (University of the Pacific)

  • James A. Uchizono

    (University of the Pacific)

  • Mamoun M. Alhamadsheh

    (University of the Pacific)

Abstract

Several investigations into the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly assumed to possess limited permeability across the blood-brain barrier. Unfortunately, the poor pharmacokinetic properties of current PAMORAs have resulted in misunderstandings of the role of central nervous system and gastrointestinal tract in precipitating side effects such as opioid-induced constipation. Here, we develop a drug delivery approach for restricting the passage of small molecules across the blood-brain barrier. This allows us to develop naloxone- and oxycodone-based conjugates that display superior potency, peripheral selectivity, pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. These probes allow us to demonstrate that the mu-opioid receptors in the central nervous system have a fundamental role in precipitating opioid-induced constipation. Therefore, our conjugates have immediate use as pharmacological probes and potential therapeutic agents for treating constipation and other opioid-related side effects.

Suggested Citation

  • Md Tariqul Haque Tuhin & Dengpan Liang & Fang Liu & Hala Aldawod & Toufiq Ul Amin & Joshua S. Ho & Rasha Emara & Arjun D. Patel & Melanie A. Felmlee & Miki S. Park & James A. Uchizono & Mamoun M. Alha, 2022. "Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31342-z
    DOI: 10.1038/s41467-022-31342-z
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    References listed on IDEAS

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    1. Aashish Manglik & Andrew C. Kruse & Tong Sun Kobilka & Foon Sun Thian & Jesper M. Mathiesen & Roger K. Sunahara & Leonardo Pardo & William I. Weis & Brian K. Kobilka & Sébastien Granier, 2012. "Crystal structure of the µ-opioid receptor bound to a morphinan antagonist," Nature, Nature, vol. 485(7398), pages 321-326, May.
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