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

7 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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title = "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 = "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.",

keywords = "Morphinan, Nalfurafine, Orexin, Ring removal, YNT-707",

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

note = "Funding Information: This work was supported by JSPS KAKENHI ( 15K16557 , 18K14352 to T.S.; 16H05098 to H.N., Y.I-T., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas ( JP15H05942 “Living in Space” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.), Japan Foundation for Applied Enzymology ( 16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Funding Information: This work was supported by JSPS KAKENHI (15K16557, 18K14352 to T.S.; 16H05098 to H.N. Y.I-T. T.S.; 18K11014 to Y.I-T. T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 ?Living in Space? to H.N.; JP17H06049 ?Willdynamics? to Y.I-T.), Japan Foundation for Applied Enzymology (16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2019.07.039",

language = "English (US)",

volume = "29",

pages = "2655--2658",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Essential structure of orexin 1 receptor antagonist YNT-707, Part IV

T2 - The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

AU - Saitoh, Tsuyoshi

AU - Seki, Kazunori

AU - Nakajima, Ryo

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

N1 - Funding Information: This work was supported by JSPS KAKENHI ( 15K16557 , 18K14352 to T.S.; 16H05098 to H.N., Y.I-T., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas ( JP15H05942 “Living in Space” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.), Japan Foundation for Applied Enzymology ( 16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Funding Information: This work was supported by JSPS KAKENHI (15K16557, 18K14352 to T.S.; 16H05098 to H.N. Y.I-T. T.S.; 18K11014 to Y.I-T. T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 ?Living in Space? to H.N.; JP17H06049 ?Willdynamics? to Y.I-T.), Japan Foundation for Applied Enzymology (16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/9/15

Y1 - 2019/9/15

N2 - 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.

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.

KW - Morphinan

KW - Nalfurafine

KW - Orexin

KW - Ring removal

KW - YNT-707

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SN - 0960-894X

VL - 29

SP - 2655

EP - 2658

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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ER -

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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