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.