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

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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.

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Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was partly supported by JSPS KAKENHI (20K05743 to T.S.; 16H05098 to H.N., Y.I-T., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.; 19K05710 to N.K.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 “Living in Space” to H.N.; JP17H06049 “Willdynamics” to Y.I-T,), Japan Foundation for Applied Enzymology (16H007 to T.S.) and Toray Industries, Inc. This work is also supported by the grant of collaborative research between University of Tsukuba and Toyota Motor

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These authors contributed equally to this work.

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