- Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor
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The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.
- Yamamoto, Naoshi,Ohrui, Sayaka,Okada, Takahiro,Yata, Masahiro,Saitoh, Tsuyoshi,Kutsumura, Noriki,Nagumo, Yasuyuki,Irukayama-Tomobe, Yoko,Ogawa, Yasuhiro,Ishikawa, Yukiko,Watanabe, Yurie,Hayakawa, Daichi,Gouda, Hiroaki,Yanagisawa, Masashi,Nagase, Hiroshi
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- Design and synthesis of KNT-127, a δ-opioid receptor agonist effective by systemic administration
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We have reported previously the novel δ-opioid agonist, SN-28, which was more potent in in vitro assays than the prototype δ-agonists, TAN-67 and SNC-80. However, when administered by subcutaneous injection, this compound showed no analgesic effect at dosages greater than 30 mg/kg in the acetic acid writhing test. We speculated that SN-28 was not effective in the test because the presence of the charged ammonium groups prevented its penetration through the blood-brain barrier. On the basis of our proposal, we designed the novel δ-agonist, KNT-127, which was effective with systemic administration.
- Nagase, Hiroshi,Nemoto, Toru,Matsubara, Ayaka,Saito, Manabu,Yamamoto, Naoshi,Osa, Yumiko,Hirayama, Shigeto,Nakajima, Mayumi,Nakao, Kaoru,Mochizuki, Hidenori,Fujii, Hideaki
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p. 6302 - 6305
(2010/11/18)
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