Effect of removal of the 14-hydroxy group on the affinity of the 4,5-epoxymorphinan derivatives for orexin and opioid receptors.

To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX1R, we prepared the 14-H and 14-dehydrated nalfurafine and their five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives. The 14-H and 14-dehydrated nalfurafine derivatives showed almost the same affinity for KOR as nalfurafine and more potent affinity for OX1R. On the other hand, 14-H and 14-dehydrated D-nor-nalfurafine derivatives showed weak affinity for KOR and almost no affinity for OX1R. The conformational analyses suggested that the 6-amide chains of the nalfurafine derivatives are mainly oriented just at or downward from the C-ring, while those of the D-nor-nalfurafine derivatives were mainly oriented toward the upper side of the C-ring even in the absence of the 14-hydroxy group. We postulated that the ion-dipole interaction between the 6-amide and the 16-nitrogen might stabilize the upwardly oriented 6-amide group. These results suggested that the 14-hydroxy group and the ion-dipole interaction would play important roles in the orientation of the 6-amide group, which might control the affinity between KOR and OX1R.

Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in d-nor-nalfurafine derivatives.

The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX1R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX1R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated d-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the d-nor-nalfurafine derivatives had a greater effect on the affinities for the OX1R than did the 14- and 17-substituents of nalfurafine derivatives.

Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine.

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.