Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437.

Mäder, Patrick; Bartholomäus, Ruben; Nicolussi, Simon; Baumann, Alice; Weis, Melanie; Chicca, Andrea; Rau, Mark; Simão, Ana Catarina; Gertsch, Jürg; Altmann, Karl-Heinz (2021). Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437. ChemMedChem, 16(1), pp. 145-154. Wiley-VCH 10.1002/cmdc.202000153

[img] Text
Synthesis JG.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (462kB) | Request a copy

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differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group.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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Nicolussi, Simon; Chicca, Andrea; Rau, Mark and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1860-7179

Publisher:

Wiley-VCH

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

06 Jul 2020 08:58

Last Modified:

11 Jan 2021 01:31

Publisher DOI:

10.1002/cmdc.202000153

PubMed ID:

32369259

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.144786

URI:

https://boris.unibe.ch/id/eprint/144786

Actions (login required)

Edit item Edit item
Provide Feedback