4.5 Article

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

Journal

CHEMMEDCHEM
Volume 16, Issue 1, Pages 145-154

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000153

Keywords

anandamide transport inhibitor; endocannabinoid membrane transport; endocannabinoid system; structure-activity relationship; WOBE437

Funding

  1. Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) TransCure

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WOBE437 is a highly potent inhibitor of endocannabinoid reuptake, and its analogues synthesized in this study showed similarly potent effects on anandamide uptake. Some of the compounds demonstrated high selectivity and significant activity differences when methoxy substituents in the head group were replaced. These compounds could serve as interesting starting points for developing potent endocannabinoid uptake inhibitors with improved drug-like properties.
WOBE437 ((2E,4E)-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differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group.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.

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