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
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
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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受体拮抗活性的巨大影响
DOI：
10.1016/j.bmcl.2017.12.069
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Nagase Hiroshi
中科院分区：
文献类型：
--
作者：
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
合成了食欲素1受体（OX1R）拮抗剂YNT-707(2)的14-脱水衍生物和14-H衍生物。得到的衍生物对OX1R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，不含14-羟基的衍生物中17-磺酰胺基团更倾向于向d环上侧取向。此外，具有6α-酰胺侧链的14-脱水衍生物的亲和力显著高于14-羟基衍生物，而相应的14-H衍生物的亲和力仅略高。因此，14-羟基强烈影响拮抗剂对OX1R的亲和力。
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.