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Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the κ-opioid receptor

Authors

  • M.J. Przydzial,

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp 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 and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp and J.R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Search for more papers by this author
  • K.E. Bosse,

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp and J.R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Search for more papers by this author
  • S.M. Andrews,

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp and J.R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Search for more papers by this author
  • T.A. Tharp,

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp and J.R. Traynor, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
    Search for more papers by this author
  • J.R. Traynor,

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp 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

    1. M.J. Przydzial, I.D. Pogozheva and H.I. Mosberg, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
      K.E. Bosse, S.M. Andrews, T.A. Tharp 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
Ann Arbor
MI 48109-1065
USA
Tel.: (734) 764-8117
Fax: (734) 763-5595
E-mail: him@umich.edu

Abstract

Abstract:  A series of cyclic, disulfide- or dithioether-containing tetrapeptides based on previously reported potent μ- and δ-selective analogs has been explored with the aim of improving their poor affinity to the κ-opioid receptor. Specifically targeted were modifications of tetrapeptide residues 3 and 4, as they presumably interact with residues from transmembrane helices 6 and 7 and extracellular loop 3 that differ among the three receptors. Accordingly, tetrapeptides were synthesized with Phe3 replaced by aliphatic (Gly, Ala, Aib, Cha), basic (Lys, Arg, homo-Arg), or aromatic sides chains (Trp, Tyr, p-NH2Phe), and with d-Pen4 replaced by d-Cys4, and binding affinities to stably expressed μ-, δ-, and κ-receptors were determined. In general, the resulting analogs failed to exhibit appreciable affinity for the κ-receptor, with the exception of the tetrapeptide Tyr-c[d-Cys-Phe-d-Cys]-NH2, cyclized via a disulfide bond, which demonstrated high binding affinity toward all opioid receptors (Kiμ = 1.26 nm, Kiδ = 16.1 nm, Kiκ = 38.7 nm). Modeling of the κ-receptor/ligand complex in the active state reveals that the receptor-binding pocket for residues 3 and 4 of the tetrapeptide ligands is smaller than that in the μ-receptor and requires, for optimal fit, that the tripeptide cycle of the ligand assume a higher energy conformation. The magnitude of this energy penalty depends on the nature of the fourth residue of the peptide (d-Pen or d-Cys) and correlates well with the observed κ-receptor binding affinity.

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