5074
H. Nagase et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5071–5074
14. Clark, J. A.; Liu, L.; Price, M.; Hersh, B.; Edelson, M.; Pasternak, G. W. J.
Pharmacol. Exp. Ther. 1989, 251, 461.
15. Nock, B. In The Pharmacology of Opioid Peptides; Tseng, L. F., Ed.; Harwood
Academic: Singapore, 1995; pp 29–56.
16. The three types of the opioid receptor have already been cloned, but to date,
the subtypes of the receptor have not been cloned. The discrepancy in the
pharmacological effects attributed to the opioid receptor subtypes may in fact
arise from activation of opioid receptor heterodimers.
17. Endoh, T.; Matsuura, H.; Tajima, A.; Izumimoto, N.; Tajima, C.; Suzuki, T.;
Saitoh, A.; Suzuki, T.; Narita, M.; Tseng, L. F.; Nagase, H. Life Sci. 1999, 65, 1685.
18. Endoh, T.; Tajima, A.; Kamei, J.; Suzuki, T.; Narita, M.; Tseng, L. F.; Nagase, H.
Eur. J. Pharmacol. 2000, 387, 133.
of nalfurafine, but these three moieties were not indispensable for
binding to the receptor. Moreover, the decahydro(iminoethan-
o)phenanthrene derivatives permitted us to determine that the
phenol ring of nalfurafine was not essential for binding to the
receptor as pharmacophores providing the hydrogen bond and
the interaction, but rather one of its key roles would be to
effectively locate the amide side chain in a favorable conformation
for the receptor binding.
j
j
p–p
j
Acknowledgments
19. Tsuji, M.; Yamazaki, M.; Takeda, H.; Matsumiya, T.; Nagase, H.; Tseng, L. F.;
Narita, M.; Suzuki, T. Eur. J. Pharmacol. 2000, 394, 91.
20. Mori, T.; Takeda, H.; Matsumiya, T.; Nagase, H.; Yamazaki, M.; Narita, M.;
Suzuki, T. Life Sci. 2000, 66, PL353.
21. Mori, T.; Nomura, M.; Yoshizawa, K.; Nagase, H.; Narita, M.; Suzuki, T. Life Sci.
2004, 75, 2473.
22. Yamaotsu, N.; Fujii, H.; Nagase, H.; Hirono, S. Bioorg. Med. Chem. 2010, 18, 4446.
23. Yamaotsu, N.; Hirono, S. Top. Curr. Chem. 2011, 299, 277.
24. Nagase, H.; Imaide, S.; Yamada, T.; Hirayama, S.; Nemoto, T.; Yamaotsu, N.;
Hirono, S.; Fujii, H. Chem. Pharm. Bull., in press.
We acknowledge the financial supports from Shorai Foundation
for Science, Uehara Memorial Foundation, and JSPS KAKENHI
(23590133) [Grant-in-Aid for Scientific Research (C)]. We also
acknowledge the Institute of Instrumental Analysis of Kitasato
University, School of Pharmacy for its facilities.
25. Casy, A. F.; Beckett, A. H. J. Pharm. Pharmacol. 1954, 6, 986.
26. Beckett, A. H. J. Pharm. Pharmacol. 1956, 8, 848.
References and notes
27. Fries, D. S. In Foye’s Principles of Medicinal Chemistry; Lemke, T. L., Williams, D.
A., Eds., 6th ed.; Lippincott Williams & Wilkins: Philadelphia, 2008; pp 652–
678.
1. Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese,
P. S.; Hamon, M. Pharmacol. Rev. 1996, 48, 567.
2. Nagase, H.; Hayakawa, J.; Kawamura, K.; Kawai, K.; Takezawa, Y.; Matsuura, H.;
Tajima, C.; Endo, T. Chem. Pharm. Bull. 1998, 46, 366.
3. 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.
4. Nakao, K.; Mochizuki, H. Drugs Today 2009, 45, 323.
5. Nagase, H.; Fujii, H. Top. Curr. Chem. 2011, 299, 29.
6. Fujii, H.; Hirayama, S.; Nagase, H. In Pharmacology; Luca, G., Ed.; InTech, 2012;
pp 81–98.
7. Lahti, R. A.; Von Voigtlander, P. F.; Barsuhn, C. Life Sci. 1982, 31, 2257.
8. Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem. 1982, 25, 1125.
9. Lahti, R. A.; Mickelson, M. M.; McCall, J. M.; Von Voigtlander, P. F. Eur. J.
Pharmacol. 1985, 109, 281.
10. Mucha, R. F.; Herz, A. Psychopharmacology 1985, 86, 274.
11. Millan, M. J. Trends Pharmacol. Sci. 1990, 11, 70.
28. Sawa, Y. K.; Tada, H. Tetrahedron 1968, 24, 6185.
29. Nemoto, T.; Fujii, H.; Nagase, H. Tetrahedron Lett. 2007, 48, 7413.
30. The stereochemistry at the 6-position in 7 or 12 was determined by 2D-NMR
experiments.
31. Osa, Y.; Ida, Y.; Yano, Y.; Furuhata, K.; Nagase, H. Heterocycles 2006, 69, 271.
32. Nagase, H.; Nemoto, T.; Matsubara, A.; Saito, M.; Yamamoto, N.; Osa, Y.;
Hirayama, S.; Nakajima, M.; Nakao, K.; Mochizuki, H.; Fujii, H. Bioorg. Med.
Chem. Lett. 2010, 20, 6302.
33. Horikiri, H.; Hirano, N.; Tanaka, Y.; Oishi, J.; Hatakeyama, H.; Kawamura, K.;
Nagase, H. Chem. Pharm. Bull. 2004, 52, 664.
34. Kawamura, K.; Horikiri, H.; Hayakawa, J.; Seki, C.; Yoshizawa, K.; Umeuchi, H.;
Nagase, H. Chem. Pharm. Bull. 2004, 52, 670.
35. Musliner, W. J.; Gates, J. W., Jr. J. Am. Chem. Soc. 1966, 88, 4271.
36. Krassnig, R.; Schmidhammer, H. Heterocycles 1994, 38, 877.
37. Ida, Y.; Nemoto, T.; Hirayama, S.; Fujii, H.; Osa, Y.; Imai, M.; Nakamura, T.;
Kanemasa, T.; Kato, A.; Nagase, H. Bioorg. Med. Chem. 2012, 20, 949.
12. Tsuji, M.; Takeda, H.; Matsumiya, T.; Nagase, H.; Narita, M.; Suzuki, T. Life Sci.
2001, 68, 1717.
13. Zukin, R. S.; Eghbali, M.; Olive, D.; Unterwald, E. M.; Tempel, A. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 4061.