Abstract
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.
Original language | English (US) |
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Article number | 128527 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 59 |
DOIs | |
State | Published - Mar 1 2022 |
Keywords
- 14-H nalfurafine
- 14-dehydration nalfurafine
- D-nor-nalfurafine
- KOR
- Structure-activity relationship
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry