Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 8, Pages 1747-1758Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.03.010
Keywords
Orexin; OX1R antagonist; Morphinan; Conformational analysis
Funding
- JSPS KAKENHI [JP16H05098, JP18K14352]
- JSPS KAKENHI (MEXT) [JP15H05942, JP17H06049, JP18K11014]
- Japan Foundation for Applied Enzymology Grant [16 T007]
- Toray Industries, Inc.
- World Premier International Research Center Initiative (WPI), Japan
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Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6 beta-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6 alpha-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6 beta-derivatives.
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