TY - JOUR
T1 - Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) library
AU - Saitoh, Tsuyoshi
AU - Amezawa, Mao
AU - Horiuchi, Jumpei
AU - Nagumo, Yasuyuki
AU - Yamamoto, Naoshi
AU - Kutsumura, Noriki
AU - Ohshita, Ryuichiro
AU - Tokuda, Akihisa
AU - Irukayama-Tomobe, Yoko
AU - Ogawa, Yasuhiro
AU - Ishikawa, Yukiko
AU - Hasegawa, Emi
AU - Sakurai, Takeshi
AU - Uchida, Yasuo
AU - Sato, Tetsu
AU - Gouda, Hiroaki
AU - Tanimura, Ryuji
AU - Yanagisawa, Masashi
AU - Nagase, Hiroshi
N1 - Funding Information:
This work was supported by JSPS KAKENHI ( 15K16557 , 18K14352, 20K05743 , 21B209 to T.S.; 16H05098 , 20H03361 to H.N., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.; 18KK0446 , 20H03399 to Y.U.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 “Living in Space” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.; JP20H05495 “Integrated Bio-metal Science” to Y.U.), Japan Foundation for Applied Enzymology ( 16H007 to T.S.), AMED under Grant Number JP21zf0127005 , and Toray Industries, Inc. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. The CD spectrum measurement was carried out with JASCO J-820 at Faculty of Pure and Applied Sciences, and the Open Facility, Research Facility Center for Science and Technology, University of Tsukuba.
Funding Information:
This work was supported by JSPS KAKENHI (15K16557, 18K14352, 20K05743, 21B209 to T.S.; 16H05098, 20H03361 to H.N. T.S.; 18K11014 to Y.I-T. T.S.; 19K07314 to Y.I-T.; 18KK0446, 20H03399 to Y.U.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 “Living in Space” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.; JP20H05495 “Integrated Bio-metal Science” to Y.U.), Japan Foundation for Applied Enzymology (16H007 to T.S.), AMED under Grant Number JP21zf0127005, and Toray Industries, Inc. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan. The CD spectrum measurement was carried out with JASCO J-820 at Faculty of Pure and Applied Sciences, and the Open Facility, Research Facility Center for Science and Technology, University of Tsukuba.
Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2022/10/5
Y1 - 2022/10/5
N2 - Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (−)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.
AB - Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (−)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.
KW - 1,3,5-Trioxazatriquinane
KW - Chemical library
KW - GPCR
KW - Orexin receptor
KW - Sleep
KW - Small molecule
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U2 - 10.1016/j.ejmech.2022.114505
DO - 10.1016/j.ejmech.2022.114505
M3 - Article
C2 - 35839689
AN - SCOPUS:85133878273
SN - 0223-5234
VL - 240
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114505
ER -