TY - JOUR
T1 - Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity
AU - Niida, Ayumu
AU - Wang, Zixuan
AU - Tomita, Kenji
AU - Oishi, Shinya
AU - Tamamura, Hirokazu
AU - Otaka, Akira
AU - Navenot, Jean Marc
AU - Broach, James R.
AU - Peiper, Stephen C.
AU - Fujii, Nobutaka
N1 - Funding Information:
This research was supported in part by 21st Century COE Program ‘Knowledge Information Infrastructure for Genome Science,’ a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science (JSPS), and the Japan Health Science Foundation. A.N. is grateful for Research Fellowships of the JSPS for Young Scientists.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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.
AB - 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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U2 - 10.1016/j.bmcl.2005.09.054
DO - 10.1016/j.bmcl.2005.09.054
M3 - Article
C2 - 16242330
AN - SCOPUS:27744543258
SN - 0960-894X
VL - 16
SP - 134
EP - 137
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 1
ER -