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

• Published in: Bioorganic & medicinal chemistry letters Vol. 59; p. 128527
• Main Authors: Katoh, Koki, Yamamoto, Naoshi, Ishikawa, Yukiko, Irukayama-Tomobe, Yoko, Tanimura, Ryuji, Saitoh, Tsuyoshi, Nagumo, Yasuyuki, Kutsumura, Noriki, Yanagisawa, Masashi, Nagase, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2022
• Subjects: 14-dehydration nalfurafine; 14-H nalfurafine; D-nor-nalfurafine; KOR; Structure-activity relationship; 14-H nalfurafine; D-nor-nalfurafine; 14-dehydration nalfurafine; Structure-activity relationship; KOR
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128527

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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.