Bioorganic & Medicinal Chemistry Letters
Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity
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Ayumu Niidaa, Zixuan Wangb, Kenji Tomitaa, Shinya Oishia, Hirokazu Tamamuraa, Akira Otakaa, Jean-Marc Navenotb, James R. Broachc, Stephen C. Peiperb and Nobutaka Fujiia, ,
bDepartment of Pathology and Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, USA
cDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Received 22 August 2005;
revised 8 September 2005;
accepted 12 September 2005.
Available online 18 October 2005.
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.
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Figure 5. GPR54-agonistic activities of metastin and metastin shortened derivatives 31–42 in lacZ reporter gene assay on yeast.
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EC50 values of several invertebrate neuropeptides for human GPR54 reported by Clements et al.
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