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Research ArticleNEUROPHARMACOLOGY

Tetrapeptide Derivatives of [d-Pen2,d-Pen5]-Enkephalin (DPDPE) Lacking an N-Terminal Tyrosine Residue Are Agonists at the μ-Opioid Receptor

Iain J. McFadyen, Katarzyna Sobczyk-Kojiro, Michael J. Schaefer, Jeffrey C. Ho, John R. Omnaas, Henry I. Mosberg and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics December 2000, 295 (3) 960-966;
Iain J. McFadyen
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Katarzyna Sobczyk-Kojiro
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Michael J. Schaefer
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Jeffrey C. Ho
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John R. Omnaas
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Henry I. Mosberg
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John R. Traynor
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Abstract

The Phe1 cyclic tetrapeptide Phe-c[d-Cys-Phe-d-Pen]NH2(Et) (JH-54) has been shown previously to exhibit high affinity and selectivity for the μ-opioid receptor. To examine the role of the Phe1 residue in the unexpected high affinity of this peptide, 11 analogs of JH-54 have been synthesized and evaluated for opioid ligand binding and for efficacy using the [35S]GTPγS assay. Alteration of the bridging groups between the d-Cys2 andd-Pen4 residues of JH-54 from dithioether to disulfide revealed the importance of the relative position of the aromatic rings of the first and third residues in determining μ- and δ-affinities. The one carbon distance between the α carbon and phenyl ring in the N-terminal residue was critical. Additional steric bulk in the N-terminal Phe1 residue was accommodated without large reductions in affinity in two naphthyl analogs, but not with 3,3-(diphenyl)alanine. Conformational restriction of the Cα-Cβ and/or Cβ-Cγ bonds had little effect on affinities in two peptides with 2-amino-2-carboxytetralin in position 1, but it abolished activity in an isoquinoline analog and differentially altered activity in four phenylproline1-containing peptides. Most surprisingly, replacement of the Phe1 aromatic ring with cyclohexyl resulted in a peptide of moderate affinity (Ki = 32.5 nM) and potency (EC50 = 58.8 nM). Thus, the tyrosylpara-hydroxyl substituent and even aromaticity in the N-terminal amino acid of these tetrapeptides are shown to be important, but not critical, features for μ-opioid receptor affinity, agonist potency, and efficacy.

Footnotes

  • Send reprint requests to: Dr. John R. Traynor, Department of Pharmacology, University of Michigan, 1301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0632. E-mail: jtraynor{at}umich.edu or Dr. Henry Mosberg, College of Pharmacy, University of Michigan, CC Little Bldg., Ann Arbor, MI 48109-1065. E-mail: him{at}umich.edu

  • ↵1 This work was supported by National Institute of Health Grants DA03910 and DA00254.

  • ↵2 These authors contributed equally to this work.

  • Abbreviations:
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    RP-HPLC
    reverse-phase high-performance liquid chromatography
    TLC
    thin-layer chromatography
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    TFA
    trifluoroacetic acid
    Atc
    2-amino-2-carboxytetralin
    Cha
    cyclohexylalanine
    Dip
    3,3-(diphenyl)alanine
    Hfe
    homophenylalanine
    1-Nal
    3-(1-naphthylalanine)
    2-Nal
    3-(2-naphthylalanine)
    Pen
    penicillamine (3,3-(dimethyl)cysteine)
    Pgl
    phenylglycine
    c-PhPro
    cis-3-phenylproline
    t-PhPro
    trans-3-phenylproline
    Tic
    1,2,3,4-tetrahydroisoquinoline 3-carboxylic acid
    Rf
    retardation factor
    Et
    –S–CH2–CH2–S–
    • Received April 28, 2000.
    • Accepted August 15, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 3
1 Dec 2000
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Research ArticleNEUROPHARMACOLOGY

Tetrapeptide Derivatives of [d-Pen2,d-Pen5]-Enkephalin (DPDPE) Lacking an N-Terminal Tyrosine Residue Are Agonists at the μ-Opioid Receptor

Iain J. McFadyen, Katarzyna Sobczyk-Kojiro, Michael J. Schaefer, Jeffrey C. Ho, John R. Omnaas, Henry I. Mosberg and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 960-966;

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Research ArticleNEUROPHARMACOLOGY

Tetrapeptide Derivatives of [d-Pen2,d-Pen5]-Enkephalin (DPDPE) Lacking an N-Terminal Tyrosine Residue Are Agonists at the μ-Opioid Receptor

Iain J. McFadyen, Katarzyna Sobczyk-Kojiro, Michael J. Schaefer, Jeffrey C. Ho, John R. Omnaas, Henry I. Mosberg and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 960-966;
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