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 |
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Affiliation: | 1. Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States;2. Program in Neuroscience, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States;3. Department of Pharmaceutical Sciences, University of Kentucky, 789 South Limestone, Lexington, KY 40506, United States;4. Research Triangle Institute, 3040 East Cornwallis Road, Research Triangle Park, NC 27709, United States |
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Abstract: | 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. |
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Keywords: | Nalfurafine Nalfurafine derivatives with 5 membered D-ring Aversion Sedation Orexin 1 receptor |
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