The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

中文翻译：

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Orexin 1受体拮抗剂YNT-707的基本结构，第五部分：17-氨基上取代基的结构-活性关系研究。

吗啡喃型orexin 1受体（OX1R）拮抗剂（例如YNT-707（2）和YNT-1310（3））显示出对OX1R的有效且极高的选择性拮抗活性。在我们研究2的基本结构的过程中，我们通过简化吗啡喃骨架确定了新的支架。然而，带有D环的新化学实体去除了支架，显示出不足的活性。为了提高这些衍生物的活性，我们研究了主要集中在17-氮基团上的取代基的作用。合成了17-N-取代的衍生物以及环状衍生物，并研究了OX1R的拮抗活性。分析结果表明，OX1R拮抗活性与17-氮上的取代基之间存在有趣的关系：随着17-取代基的体积增加，拮抗活性也增加。最后，17-N-Boc衍生物14a显示出最有效的OX1R拮抗活性（Ki = 14.8 nM）。