Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Tsuyoshi Saitoh; Kazunori Seki; Ryo Nakajima; Naoshi Yamamoto; Noriki Kutsumura; Yasuyuki Nagumo; Yoko Irukayama-Tomobe; Yasuhiro Ogawa; Yukiko Ishikawa; Ryuji Tanimura; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2019.07.039

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Tsuyoshi Saitoh, Kazunori Seki, Ryo Nakajima, Naoshi Yamamoto, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

The orexin 1 receptor (OX₁R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX₁R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX₁R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX₁R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX₁R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX₁R ligands.

Original language	English (US)
Pages (from-to)	2655-2658
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2019.07.039
State	Published - Sep 15 2019

Keywords

Morphinan
Nalfurafine
Orexin
Ring removal
YNT-707

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.07.039

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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. (2019). Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity. Bioorganic and Medicinal Chemistry Letters, 29(18), 2655-2658. https://doi.org/10.1016/j.bmcl.2019.07.039

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity. / Saitoh, Tsuyoshi; Seki, Kazunori; Nakajima, Ryo et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 18, 15.09.2019, p. 2655-2658.

Research output: Contribution to journal › Article › peer-review

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 2019, 'Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 18, pp. 2655-2658. https://doi.org/10.1016/j.bmcl.2019.07.039

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abstract = "The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.",

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AU - Seki, Kazunori

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AU - Yamamoto, Naoshi

AU - Kutsumura, Noriki

AU - Nagumo, Yasuyuki

AU - Irukayama-Tomobe, Yoko

AU - Ogawa, Yasuhiro

AU - Ishikawa, Yukiko

AU - Tanimura, Ryuji

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

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AB - The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

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Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

Abstract

Keywords

ASJC Scopus subject areas

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