食欲素1受体拮抗剂YNT - 707的基本结构，第二部分：14 - 羟基对食欲素1受体拮抗活性的显著影响。
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.
作者信息
Ohrui Sayaka, Yamamoto Naoshi, Saitoh Tsuyoshi, Kutsumura Noriki, Nagumo Yasuyuki, Irukayama-Tomobe Yoko, Ogawa Yasuhiro, Ishikawa Yukiko, Watanabe Yurie, Hayakawa Daichi, Gouda Hiroaki, Yanagisawa Masashi, Nagase Hiroshi
机构信息
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
出版信息
Bioorg Med Chem Lett. 2018 Feb 15;28(4):774-777. doi: 10.1016/j.bmcl.2017.12.069. Epub 2017 Dec 30.
The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OXR) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OXR 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 OXR.
合成了食欲素1受体（OXR）拮抗剂YNT-707（2）的14-脱水和14-H衍生物。所得到的衍生物对OXR的亲和力高于相应的14-羟基衍生物。构象分析表明，与14-羟基衍生物相比，没有14-羟基的衍生物中的17-磺酰胺基团更倾向于朝向D环的上侧。此外，具有6α-酰胺侧链的14-脱水衍生物显示出比14-羟基衍生物显著更高的亲和力，而相应的14-H衍生物仅显示出略高的亲和力。因此，14-羟基基团强烈影响拮抗剂对OXR的亲和力。
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