Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis

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Abstract

A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2 receptors, respectively, was discovered. A comparative study to compare solid-phase and solution-phase chemistries for the efficient synthesis of the active class, tetracyclic benzimidazoles, was undertaken. The solid-phase chemistry was found to be superior both for the synthesis of analogs and for the synthesis of gram quantities.

Graphical abstract

A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2, respectively, receptors was discovered.

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Acknowledgment

We thank Mrs. Sine Mandrup Bertozzi for analytical assistance.

References and notes (12)

  • X. Dong et al.

    Cell

    (2001)
  • N. Robas et al.

    J. Biol. Chem.

    (2003)
  • A.D. Spier et al.

    Brain Res. Rev.

    (2000)
  • M. Kamohara et al.

    Biochem. Biophys. Res. Commun.

    (2005)
  • L. Zhang et al.

    Mol. Brain. Res.

    (2005)
  • P. Kunapuli et al.

    Anal. Biochem.

    (2006)
There are more references available in the full text version of this article.

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