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Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437
Author(s) -
Mäder Patrick,
Bartholomäus Ruben,
Nicolussi Simon,
Baumann Alice,
Weis Melanie,
Chicca Andrea,
Rau Mark,
Simão Ana Catarina,
Gertsch Jürg,
Altmann KarlHeinz
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000153
Subject(s) - anandamide , fatty acid amide hydrolase , endocannabinoid system , chemistry , stereochemistry , cannabinoid , enzyme , cannabinoid receptor , enzyme inhibitor , natural product , biochemistry , pharmacology , biology , antagonist , receptor
WOBE437 ((2 E ,4 E )‐N‐(3,4‐dimethoxyphenethyl)dodeca‐2,4‐dienamide, 1 ) is a natural product‐derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 ( 1 ). At the same time, a number of WOBE437 variants exhibited potencies in the sub‐100 nM range, with high selectivity over inhibition of the endocannabinoid‐degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1 . Interestingly, profound activity differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug‐like properties.