Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity

Ayumu Niida, Zixuan Wang, Kenji Tomita, Shinya Oishi, Hirokazu Tamamura, Akira Otaka, Jean Marc Navenot, James R. Broach, Stephen C. Peiper, Nobutaka Fujii

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Abstract

Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and d-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors.

Original languageEnglish (US)
Pages (from-to)134-137
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2006

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Niida, A., Wang, Z., Tomita, K., Oishi, S., Tamamura, H., Otaka, A., Navenot, J. M., Broach, J. R., Peiper, S. C., & Fujii, N. (2006). Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity. Bioorganic and Medicinal Chemistry Letters, 16(1), 134-137. https://doi.org/10.1016/j.bmcl.2005.09.054