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Design of high affinity cyclic pentapeptide ligands for κ-opioid receptors

Authors

  • M.J. Przydzial,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • I.D. Pogozheva,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • J.C. Ho,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • K.E. Bosse,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • E. Sawyer,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • J.R. Traynor,

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
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  • H.I. Mosberg

    1. M.J. Przydzial, I.D. Pogozheva, J.C. Ho and H.I. Mosberg, Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
      K. E. Bosse, E. Sawyer and J. R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Search for more papers by this author

H.I. Mosberg
Department of Medicinal Chemistry
College of Pharmacy
University of Michigan
428 Church St
Ann Arbor
MI 48109-1065
USA
Tel.: (734) 764-8117
Fax: (734) 763-5595
E-mail: him@umich.edu

Abstract

Abstract:  Using results from our previously reported cyclic opioid peptide series and reliable models for μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR, respectively) and their complexes with peptide ligands, we have designed and synthesized a series of cyclic pentapeptides of structure Tyr-c[d-Cys-Phe-Phe-X]-NH2, cyclized via disulfide, methylene, or ethylene dithioethers, and where X = d- or l-Cys; or d- or l-penicillamine (Pen; β,β-dimethylcysteine). Determination of binding affinities to MOR, DOR, and KOR revealed that members of this series with X = d- or l-Cys display KOR affinities in the low nanomolar range, demonstrating that a ‘DPDPE-like’ tetrapeptide scaffold is suitable not only for DOR and MOR ligands, but also for KOR ligands. The cyclic pentapeptides reported here are not, however, selective for KOR, rather they display significant selectivity and high affinity for MOR. Indeed, peptide 8, Tyr-c[d-Cys-Phe-Phe-Cys]-NH2-cyclized via a methylene dithioether, shows picomolar binding affinity for MOR (inline image = 16 pm) with more than 100-fold selectivity for MOR vs. DOR or KOR, and may be of interest as a high affinity, high selectivity MOR ligand. Nonetheless, the high affinity KOR peptides in this series represent excellent leads for the development of structurally related, selective KOR ligands designed to exploit structurally specific features of KOR, MOR, and DOR.

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