孤啡肽受体拮抗剂 YNT-707 的基本结构，第四部分：D 环在 4,5-环氧吗啡烷对孤啡肽 1 受体拮抗活性中的作用。
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.
机构信息
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
出版信息
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2655-2658. doi: 10.1016/j.bmcl.2019.07.039. Epub 2019 Jul 24.
The orexin 1 receptor (OXR) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OXR. In the course of our study of the essential structure of YNT-707 for high binding affinity against OXR, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OXR 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 OXR antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OXR ligands.
携带吗啡烷骨架的食欲素 1 受体（OXR）拮抗剂，如 YNT-707（2）和 YNT-1310（3），对 OXR 表现出强大且极高的选择性拮抗活性。在研究 YNT-707 对 OXR 高结合亲和力的基本结构的过程中，我们制备了没有 D-和 4,5-环氧环的 2 的衍生物，以阐明这些结构决定因素对 OXR 拮抗活性的作用。D-和 4,5-环氧环对于 17-磺酰胺和 6-酰胺侧链的活性取向起着重要作用。最后，我们确定了在复杂的吗啡烷骨架中选择性 OXR 拮抗活性所需的简单结构，这有望成为进一步设计 OXR 配体的有用支架。
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