Format

Send to

Choose Destination
Biochem Pharmacol. 2018 Jun;152:129-142. doi: 10.1016/j.bcp.2018.03.018. Epub 2018 Mar 21.

Structure-kinetic relationship studies of cannabinoid CB2 receptor agonists reveal substituent-specific lipophilic effects on residence time.

Author information

1
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands; Department of Molecular Physiology, Leiden Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands.
2
Department of Molecular Physiology, Leiden Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands.
3
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands. Electronic address: l.h.heitman@lacdr.leidenuniv.nl.

Abstract

A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB2 receptor (CB2R), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases. Here, we have investigated the relationships between physicochemical properties, binding kinetics and functional activity in two different signal transduction pathways, G protein activation and β-arrestin recruitment. We synthesized 24 analogues of 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazoleidine-2,4-dione (LEI101), our previously reported in vivo active and CB2R-selective agonist, with varying basicity and lipophilicity. We identified a positive correlation between target residence time and functional potency due to an increase in lipophilicity on the alkyl substituents, which was not the case for the amine substituents. Basicity of the agonists did not show a relationship with affinity, residence time or functional activity. Our findings provide important insights about the effects of physicochemical properties of the specific substituents of this scaffold on the binding kinetics of agonists and their CB2R pharmacology. This work therefore shows how CB2R agonists can be designed to have optimal kinetic profiles, which could aid the lead optimization process in drug discovery for the study or treatment of inflammatory diseases.

KEYWORDS:

Cannabinoid CB(2) receptor; Functional potency; Physicochemical properties; Target residence time

PMID:
29574067
DOI:
10.1016/j.bcp.2018.03.018
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center