Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

Author(s):
Mohr, F.; Hurrle, T.; Burggraaff, L. (0000-0002-2442-0443); Langer, L.; Bemelmans, M.P.; Knab, M.; Nieger, M.; Westen, G.J.P. van (0000-0003-0717-1817); Heitman, L.H. (0000-0002-1381-8464); Bräse, S.
Published
2021
Publication type
Article / Letter to editor

Abstract

We report the development and extensive structure-activity relationship evaluation of a series of

modified coumarins as cannabinoid receptor ligands. In radioligand, and [35S]GTPgS binding assays the

CB receptor binding affinities and efficacies of the new ligands were determined. Furthermore, we used a

ligand-based docking approach to validate the empirical observed results. In conclusion, several crucial structural requirements were identified. The most potent coumarins like 3-butyl-7-(1-butylcyclopentyl)- 5-hydroxy-2H-chromen-2-one (36b, Ki CB2 13.7 nM, EC50 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3- propyl-2H-chromen-2-one (39b, Ki CB2 6.5 nM, EC50 4.51 nM) showed a CB2 selective agonistic profile with low nanomolar affinities.

CB receptorsSynthetic cannabinoidsCoumarinsCB2 agonistsEndocannabinoid systemRadioligand binding assays
Date issued
2021-04-07
Language
English
Publisher
Elsevier BV
Is part of
European Journal of Medicinal Chemistry
hdl
1887/3209595
doi
10.1016/j.ejmech.2021.113354