Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437.
WOBE437
anandamide transport inhibitor
endocannabinoid membrane transport
endocannabinoid system
structure-activity relationship
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
08 01 2021
08 01 2021
Historique:
received:
10
03
2020
revised:
02
05
2020
pubmed:
6
5
2020
medline:
18
9
2021
entrez:
6
5
2020
Statut:
ppublish
Résumé
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differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group.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.
Identifiants
pubmed: 32369259
doi: 10.1002/cmdc.202000153
doi:
Substances chimiques
Amides
0
Cannabinoid Receptor Agonists
0
Receptors, Cannabinoid
0
Amidohydrolases
EC 3.5.-
fatty-acid amide hydrolase
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
145-154Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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