リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Structure-activity relationship study of morphinan-type orexin 1 receptor antagonist: Role of ring structures and substituent effect of the 17-amino group」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Structure-activity relationship study of morphinan-type orexin 1 receptor antagonist: Role of ring structures and substituent effect of the 17-amino group

関, 知範 筑波大学 DOI:10.15068/00160438

2020.07.21

概要

Previous studies regarding the essential structure of YNT-707 have mainly discussed the role and configuration of the side chains and their effects on the selective OX1R antagonistic activity. However, to date, the influence of the morphinan skeleton on the activity and selectivity for OX1R has not been investigated thoroughly. The conversion of the morphinan skeleton require the use of a costly starting material (naltrexone·HCl, ¥113,700/g from Sigma-Aldrich) and skilled laboratory techniques (Fig. 10). Therefore, the structural transformation of the morphinan skeleton to a new scaffold was deemed important for further drug discovery in the area of OX1R antagonists. In the current thesis, a novel structure-activity relationship study was carried out to obtain a structural insight into the significance of the morphinan skeleton for designing a new simple scaffold.

Chapter 2 describes the design and synthesis of the YNT-707 derivatives without the D- and E-rings to clarify the role of these moieties in the morphinan skeleton (Fig. 11).29 Moreover, the effects of the 14-hydroxy group as well as the configuration of the 6-amide side chain in these analogs were also investigated with a view to obtaining a less complex structure.

Although the synthesized simpler derivatives displayed moderate selective OX1R antagonistic activity (chapter 2), the potencies of these analogs were not sufficient for further pharmacological investigation or the design of alternative scaffolds. Thus, to improve the activities, chapter 3 describes the investigation of the substituent effects on the 17-nitrogen group in the less complex analogs (Fig. 12).

論文の公開元へ

関連論文

関連論文をもっと見る

参考文献

1) Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R. M.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J. R.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu, W. S.; Terrett, J. A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998, 92, 573−585.

2) de Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.; Foye, P. E.; Danielson, P. E.; Fukuhara, C.; Battenberg, E. L.; Gautvik, V. T.; Bartlett, F. S., 2nd; Frankel, W. N.; van den Pol, A. N.; Bloom, F. E.; Gautvik, K. M.; Sutcliffe, J. G. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 322−327.

3) Lin, L.; Faraco, F.; Li, R.; Kadotani, H.; Rogers, W.; Lin, X.; Qiu, X.; de Jong, P. J.; Nishino, S.; Mignot, E. Cell 1999, 98, 365−376.

4) Chemelli, R. M.; Willie, J. T.; Sinton, C. M.; Elmquist, J. K.; Scammell, T.; Lee, C.; Richardson, J. A.; Williams, S. C.; Xiong, Y.; Kisanuki, Y.; Fitch, T. E.; Nakazato, M.; Hammer, R. E.; Saper, C. B.; Yanagisawa, M. Cell 1999, 98, 437−451.

5) Sakurai, T. Nat. Rev. Neurosci. 2014, 15, 719−731.

6) (a) Mahler, S. V.; Smith, R. J.; Moorman, D. E.; Sartor, G. C.; Aston-Jones, G. Prog. Brain Res. 2012, 198, 79−121. (b) Baimel, C.; Bartlett, S. E.; Chiou, L.-C.; Lawrence, A. J.; Muschamp, J. W.; Patkar, O.; Tung, L.-W.; Borgland, S. L. Br. J. Pharmacol. 2015, 172, 334−348.

7) (a) Harris, G. C.; Wimmer, M.; Aston-Jones, G. Nature 2005, 437, 556−559. (b) Borgland, S. L.; Taha, S. A.; Sarti, F.; Fields, H. L.; Bonci, A. Neuron 2006, 49, 589−601. (c) España, R. A.; Melchior, J. R.; Roberts, D. C.; Jones, S. R. Psychopharmacol. 2011, 214, 415−426.

8) Harris, G. C.; Wimmer, M.; Randall-Thompson, J. F.; Aston-Jones, G. Behav. Brain Res. 2007, 183, 43−51.

9) (a) Quarta, D.; Valerio, E.; Hutcheson, D. M.; Hedou, G.; Heidbreder, C. Neurochem. Int. 2010, 56, 11−15. (b) Winrow, C. J.; Tanis, K. Q.; Reiss, D. R.; Rigby, A. M.; Uslaner, J. M.; Uebele, V. N.; Doran, S. M.; Fox, S. V.; Garson, S. L.; Gotter, A. L.; Levine, D. M.; Roecker, A. J.; Coleman, P. J.; Koblan, K. S.; Renger, J. J. Neuropharmacol. 2010, 58, 185−194.

10) Smith, R. J.; Aston-Jones, G. Eur. J. Neurosci. 2012, 35, 798−804.

11) (a) Pasumarthi, R. K.; Reznikov, L. R.; Fadel, J. Eur. J. Pharmacol. 2006, 535, 172−176. (b) Hollander, J. A.; Lu, Q.; Cameron, M. D.; Kamenecka, T. M.; Kenny, P. J. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 19480−19485. (c) Plaza-Zabala, A.; Martin-Garcia, E.; de Lecea, L.; Maldonado, R.; Berrendero, F. J. Neurosci. 2010, 30, 2300−2310. (d) Plaza-Zabala, A.; Flores, Á.; Maldonado, R.; Berrendero, F. Biol. Psychiatry 2012, 71, 214−223.

12) (a) Lawrence, A. J.; Cowen, M. S.; Yang, H. J.; Chen, F.; Oldfield, B. Br. J. Pharmacol. 2006, 148, 752−759. (b) Dayas, C. V.; McGranahan, T. M.; Martin-Fardon, R.; Weiss, F. Biol. Psychiatry 2008, 63, 152−157. (c) Richards, J. K.; Simms, J. A.; Steensland, P.; Taha, S. A.; Borgland, S. L.; Bonci, A.; Bartlett, S. E. Psychopharmacol. 2008, 199, 109−117. (d) Moorman, D. E.; Aston-Jones, G. Alcohol 2009, 43, 379−386. (e) Jupp, B.; Krstew, E.; Dezsi, G.; Lawrence, A. J. Br. J. Pharmacol. 2011, 162, 880−889. (f) Kim, A. K.; Brown, R. M.; Lawrence, A. J. Front. Behav. Neurosci. 2012, 6, 78. (g) Srinivasan, S.; Simms, J. A.; Nielsen, C. K.; Lieske, S. P.; Bito-Onon, J. J.; Yi, H.; Hopf, F. W.; Bonci, A.; Bartlett, S. E. PLoS One 2012, 7, e44726.

13) Flores, A.; Maldonado, R.; Berrendero, F. Front. Neurosci. 2013, 7, 1−17.

14) (a) Roecker A.; Cox, C.; Coleman, P. J. Med. Chem. 2016, 59, 504–530. (b) Boss, C.; Roch, C. Bioorg. Med. Chem. Lett. 2015, 25, 2875–2887. (c) Lebold, T. P.; Bonaventure, P.; Shireman, B. T. Bioorg. Med. Chem. Lett. 2013, 23, 4761–4769.

15) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.; McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Reiss, D. R.; Harrell, C. M.; Murphy, K. L.; Garson, S. L.; Doran, S. M.; Prueksaritanont, T.; Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.; Hartman, G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. J. Med. Chem. 2010, 53, 5320–5332.

16) (a) Yoshida, Y.; Naoe, Y.; Terauchi, T.; Ozaki, F.; Doko, T.; Takemura, A.; Tanaka, T.; Sorimachi, K.; Beuckmann, C. T.; Suzuki, M.; Ueno, T.; Ozaki, S.; Yonaga, M. J. Med. Chem. 2015, 58, 4648–4664. (b) Beuckmann, C. T.; Suzuki, M.; Ueno, T.; Nagaoka, K.; Arai, T.; Higashiyama, H. J. Pharmacol. Exp. Ther. 2017, 362, 287–295.

17) Haynes, A. C.; Jackson, B.; Chapman, H.; Tadayyon, M.; Johns, A.; Porter, R. A.; Arch, J. R. S. Regul. Pept. 2000, 96, 45−51.

18) Langmead, C. J.; Jerman, J. C.; Brough, S. J.; Scott, C.; Porter, R. A.; Herdon, H. J. Br. J. Pharmacol. 2004, 141, 340−346.

19) Steiner, M. A.; Gatfield, J.; Brisbare-Roch, C.; Dietrich, H.; Treiber, A.; Jenck, F.; Boss, C. ChemMedChem 2013, 8, 898–903.

20) Raheem, I. T.; Breslin, M. J.; Bruno, J.; Cabalu, T. D.; Cooke, A.; Cox, C. D.; Cui, D.; Garson, S.; Gotter, A. L.; Fox, S. V.; Harrell, C. M.; Kuduk, S. D.; Lemaire, W.; Prueksaritanont, T.; Renger, J. J.; Stump, C.; Tannenbaum, P. L.; Williams, P. D.; Winrow, C. J.; Coleman, P. J. Bioorg. Med. Chem. 2015, 25, 444– 450.

21) Futamura, A.; Nozawa, D.; Araki, Y.; Tamura, Y.; Tokura, S.; Kawamoto, H.; Tokumaru, Y.; Kakihara, S.; Aoki, T.; Ohtake, N. Bioorg. Med. Chem. 2017, 25, 5203–5215.

22) Chou, T. C.; Lee, C. E.; Elmquist, J. K.; Hara, J.; Willie, J. T.; Beuckmann, C. T.; Chemelli, R. M.; Sakurai, T.; Yanagisawa, M.; Saper, C. B.; Scammel, T. E. J. Neurosci. 2001, 21, RC168.

23) Chen, J.; Zhang, R.; Chen, X.; Wang, C.; Cai, X.; Liu, H.; Jiang, Y.; Liu, C.; Bai, B. Cell. Signalling 2015, 27, 1426−1438.

24) (a) Nagase, H.; Hayakawa, J.; Kawamura, K.; Kawai, K.; Takezawa, Y.; Matsuura, H.; Tajima, C.; Endo, T. Chem. Pharm. Bull. 1998, 46, 366−369. (b) Kawai, K.; Hayakawa, J.; Miyamoto, T.; Imamura, Y.; Yamane, S.; Wakita, H.; Fujii, H.; Kawamura, K.; Matsuura, H.; Izumimoto, N.; Kobayashi, R.; Endo, T.; Nagase, H. Bioorg. Med. Chem. 2008, 16, 9188−9201. (c) Nagase, H.; Fujii, H. Top. Curr. Chem. 2010, 299, 29−62. (d) Nagase, H.; Fujii, H. Top. Curr. Chem. 2010, 299, 187−237. (e) Nagase, H.; Fujii, H. Curr. Pharm. Des. 2013, 19, 7400−7414. (f) Nagase, H.; Kutsumura, N. Arch. Pharm. 2015, 348, 375−389.

25) Nagase, H.; Yamamoto, N.; Yata, M.; Ohrui, S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ishikawa, Y.; Ogawa, Y.; Hirayama, S.; Kuroda, D.; Watanabe, Y.; Gouda, H.; Yanagisawa, M. J. Med. Chem. 2017, 60, 1018−1040.

26) Yamamoto N.; Ohrui, S.; Okada, T.; Yata, M.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H. Bioorg. Med. Chem. Lett. 2017, 27, 4176−4179.

27) Ohrui S.; Yamamoto N.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H. Bioorg. Med. Chem. Lett. 2018, 28, 774−777.

28) Yamamoto N.; Ohrui S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H. Bioorg. Med. Chem. 2019, 27, 1747−1758.

29) Saitoh, T.; Seki, K.; Nakajima, R.; Yamamoto, N.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Tanimura, R.; Yanagisawa, M.; Nagase, H. Bioorg. Med. Chem. Lett. 2019, 29, 2655−2658.

30) Saitoh, T.; Seki, K.; Nakajima, R.; Yamamoto, N.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Yanagisawa, M.; Nagase, H. Bioorg. Med. Chem. Lett. in press, doi: 10.1016/j.bmcl.2020.126893.

31) Fujii, H.; Imaide, S.; Watanabe, A.; Yoza, K.; Nakajima, M.; Nakao, K.; Mochizuki, H.; Sato, N.; Nemoto, T.; Nagase, H. J. Org. Chem. 2010, 75, 995–998.

32) Fujii, H.; Imaide, S.; Watanabe, A.; Nemoto, T.; Nagase, H. Tetrahedron. Lett. 2008, 49, 6293–6296.

33) The antagonistic effect was evaluated by the measurement of the intercellular Ca2+ concentration indicated by the fluorescence change of Fura 2-AM after the treatment of OXA (300 pM) with chinese hamster ovary (CHO) cells overexpressing human OX1R or OX2R pre-treated with synthetic compounds.

34) Nagahara, T.; Saitoh, T.; Kutsumura, N.; Irukayama-Tomobe, Y.; Ogawa, Y.; Kuroda, D.; Gouda, H.; Kumagai, H.; Fujii, H.; Yanagisawa, M.; Nagase, H. J. Med. Chem. 2015, 58, 7931−7937.

35) Yamamoto, N.; Fujii, H.; Imaide, S.; Hirayama, S.; Nemoto, T.; Inokoshi, J.; Tomoda, H.; Nagase, H. J. Org. Chem. 2011, 76, 2257–2260.

36) The conformational analysis was conducted using the Conformational Search function in the MOE software package ver. 2018.0101 (Chemical Computing Group, Inc., Montreal, Canada) with LowModeMD method, MMFF94x force field, gas-phase electrostatics, and no nonbonded interaction cutoff.

37) Compounds that are not shown in schemes are numbered as ES-#.

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文
を
一発検索！

この論文の関連論文を見る