Structure-Guided Preference Feeding Behavioral Responses of Coumarin Analogs in Caenorhabditis elegans

Coumarins are a group of naturally occurring phytochemicals found in various plants with many bioactivities. Recently, it was reported that esculetin (6,7-dihydroxycoumarin) reduced food preference behavior of Caenorhabditis elegans dependent on the human µ-opioid receptor (MOPR). Thus, this study investigated the structure-activity relationships (SAR) of 17 coumarin analogs using a food preference assay in C. elegans. While the parent compound, coumarin, and single substitutions at C3, C5, C7, or C8 had no effect, modifications at C4 and C6 were critical for modulating this behavior. Specifically, 4-hydroxycoumarin, 4-methylcoumarin, 6-hydroxycoumarin, 4-hydroxy-6-methylcoumarin, 6,7-dihydroxycoumarin (esculetin), 7-hydroxy-6-methoxycoumarin (scopoletin), and several di-substituted derivatives significantly reduced the preference index, which was abolished in npr-17 (opioid receptor homolog) knockout strains. Additional determination of preference behaviors was conducted with a strain carrying the human MOPR, which showed results comparable to the wildtype, except for 4-hydroxy-6-methylcoumarin and scopoletin. This work demonstrates the potential antagonistic effects of selected coumarins and the utility of C. elegans as an in vivo model for SAR studies targeting human MOPR.