Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

Sayaka Ohrui; Naoshi Yamamoto; Tsuyoshi Saitoh; Noriki Kutsumura; Yasuyuki Nagumo; Yoko Irukayama-Tomobe; Yasuhiro Ogawa; Yukiko Ishikawa; Yurie Watanabe; Daichi Hayakawa; Hiroaki Gouda; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2017.12.069

Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

Sayaka Ohrui, Naoshi Yamamoto, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase

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

13 Scopus citations

Abstract

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX₁R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX₁R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX₁R.

Original language	English (US)
Pages (from-to)	774-777
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2017.12.069
State	Published - Feb 15 2018

Keywords

4,5-Epoxymorphinan
Conformational study
OX1R antagonist
Orexin
YNT-707

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2017.12.069

Cite this

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. (2018). Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity. Bioorganic and Medicinal Chemistry Letters, 28(4), 774-777. https://doi.org/10.1016/j.bmcl.2017.12.069

Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity. / Ohrui, Sayaka; Yamamoto, Naoshi; Saitoh, Tsuyoshi et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 4, 15.02.2018, p. 774-777.

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

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 2018, 'Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 4, pp. 774-777. https://doi.org/10.1016/j.bmcl.2017.12.069

@article{319c0b65f25840a79cbd3964e3fdc333,

title = "Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity",

abstract = "The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.",

keywords = "4,5-Epoxymorphinan, Conformational study, OX1R antagonist, Orexin, YNT-707",

author = "Sayaka Ohrui and Naoshi Yamamoto and Tsuyoshi Saitoh and Noriki Kutsumura and Yasuyuki Nagumo and Yoko Irukayama-Tomobe and Yasuhiro Ogawa and Yukiko Ishikawa and Yurie Watanabe and Daichi Hayakawa and Hiroaki Gouda and Masashi Yanagisawa and Hiroshi Nagase",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = feb,

day = "15",

doi = "10.1016/j.bmcl.2017.12.069",

language = "English (US)",

volume = "28",

pages = "774--777",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "4",

}

TY - JOUR

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

T2 - Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

AU - Ohrui, Sayaka

AU - Yamamoto, Naoshi

AU - Saitoh, Tsuyoshi

AU - Kutsumura, Noriki

AU - Nagumo, Yasuyuki

AU - Irukayama-Tomobe, Yoko

AU - Ogawa, Yasuhiro

AU - Ishikawa, Yukiko

AU - Watanabe, Yurie

AU - Hayakawa, Daichi

AU - Gouda, Hiroaki

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

PY - 2018/2/15

Y1 - 2018/2/15

N2 - The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

AB - The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

KW - 4,5-Epoxymorphinan

KW - Conformational study

KW - OX1R antagonist

KW - Orexin

KW - YNT-707

UR - http://www.scopus.com/inward/record.url?scp=85040469224&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040469224&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2017.12.069

DO - 10.1016/j.bmcl.2017.12.069

M3 - Article

C2 - 29338909

AN - SCOPUS:85040469224

SN - 0960-894X

VL - 28

SP - 774

EP - 777

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 4

ER -

Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this