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

Florian Mohr; Thomas Hurrle; Lindsey Burggraaff; Lukas Langer; Martijn P Bemelmans; Maximilian Knab; Martin Nieger; Gerard J P van Westen; Laura H Heitman; Stefan Bräse

doi:10.1016/j.ejmech.2021.113354

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

Eur J Med Chem. 2021 Aug 5:220:113354. doi: 10.1016/j.ejmech.2021.113354. Epub 2021 Apr 7.

Authors

Affiliations

¹ Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, the Netherlands.
² Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344, Eggenstein-Leopoldshafen, Germany.
³ Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, the Netherlands.
⁴ Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany.
⁵ Department of Chemistry, University of Helsinki, P.O. Box 55 (A. I. Virtasen Aukio 1), 00014, Finland.
⁶ Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, the Netherlands. Electronic address: l.h.heitman@chem.leidenuniv.nl.
⁷ Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344, Eggenstein-Leopoldshafen, Germany. Electronic address: braese@kit.edu.

PMID: 33915369
DOI: 10.1016/j.ejmech.2021.113354

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]GTPγS 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, K_i CB₂ 13.7 nM, EC₅₀ 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, K_i CB₂ 6.5 nM, EC₅₀ 4.51 nM) showed a CB₂ selective agonistic profile with low nanomolar affinities.

Keywords: CB receptors; CB(2) agonists; Coumarins; Endocannabinoid system; Radioligand binding assays; Synthetic cannabinoids.

MeSH terms

Animals
CHO Cells
Cannabinoid Receptor Agonists / chemical synthesis
Cannabinoid Receptor Agonists / chemistry
Cannabinoid Receptor Agonists / pharmacology*
Cells, Cultured
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Cricetulus
Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation
Molecular Structure
Receptors, Cannabinoid / metabolism*
Structure-Activity Relationship

Substances

Cannabinoid Receptor Agonists
Coumarins
Receptors, Cannabinoid