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Related Experiment Videos

Cyclic peptides as selective tachykinin antagonists

B J Williams1, N R Curtis, A T McKnight

  • 1Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England.

Journal of Medicinal Chemistry
|January 8, 1993
PubMed
Summary

Researchers developed novel cyclic peptides targeting substance P receptors. Five compounds showed high tachykinin antagonist activity at NK-2 receptors, with two potent and selective candidates identified for further study.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Peptide Science

Background:

  • Substance P is a neuropeptide involved in various physiological processes.
  • Tachykinin receptors, including NK-2, are targets for therapeutic intervention.
  • Cyclic peptides offer conformational rigidity and potential for receptor selectivity.

Purpose of the Study:

  • To design and synthesize novel homodetic cyclic peptides based on the C-terminal sequence of substance P.
  • To evaluate the tachykinin antagonist activity of these cyclic peptides at NK-2 receptors.
  • To identify potent and selective NK-2 receptor antagonists.

Main Methods:

  • Solid-phase peptide synthesis techniques were employed.
  • Azide coupling procedures were utilized for cyclization.

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  • Incorporation of gamma-lactam dipeptide mimics to restrict conformational mobility.
  • Pharmacological evaluation of receptor binding and antagonist activity (pA2 values) in rat vas deferens preparations.

    • Main Results:

    • Twenty homodetic cyclic peptides were successfully synthesized.
    • Five cyclic peptides exhibited high tachykinin antagonist activity (pA2 > 6) at NK-2 receptors.
    • Two compounds, XVII (pA2 = 8.1) and I (pA2 = 6.7), demonstrated the highest potency.
    • These potent compounds showed selectivity for NK-2 receptors over other tachykinin receptors.

    Conclusions:

    • Novel cyclic peptides based on substance P's C-terminus can be effectively synthesized.
    • Certain cyclic peptides possess significant tachykinin antagonist activity at NK-2 receptors.
    • The most potent cyclic peptides identified are selective for NK-2 receptors, representing promising leads for drug development.