The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX₁Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX₁R. The dual affinities of 1 for OX₁R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX₁R knockout mice, but not in wild-type mice. These results well support that OX₁R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.

D-nor-呋喃酮衍生物是通过纳氟拉芬（6）中的六元D环收缩而合成的，对orexin 1受体（OX ₁ Rs）没有亲和力。17 Ñ在-lone电子对1取向朝向轴向方向，而d去甲衍生物的在赤道构定向。轴向孤电子对可与14-羟基形成氢键，可将6-酰胺侧链推向相对于C环的向下方向。所得构象将是与OX ₁ R结合的活性构象。1对OX ₁的双重亲和力R和κ阿片受体（KOR）使我们阐明了只有1个没有厌恶而是U-50488H的机制。实际上，1在OX ₁ R敲除小鼠中选择性诱导严重厌恶，而在野生型小鼠中则没有。这些结果很好地支持该OX ₁ - [R抑制的厌恶1。这是长期难题的阐明，其中1没有显示出KOR的反感。