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

Marjolein Soethoudt; Mark W H Hoorens; Ward Doelman; Andrea Martella; Mario van der Stelt; Laura H Heitman

doi:10.1016/j.bcp.2018.03.018

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

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

Authors

Marjolein Soethoudt¹, Mark W H Hoorens², Ward Doelman², Andrea Martella², Mario van der Stelt², Laura H Heitman³

Affiliations

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.

PMID: 29574067
DOI: 10.1016/j.bcp.2018.03.018

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cannabinoid Receptor Agonists / chemical synthesis*
Cannabinoid Receptor Agonists / chemistry
Cannabinoid Receptor Agonists / pharmacology*
Cell Line
Cricetinae
Humans
Imidazolidines / chemistry*
Imidazolidines / pharmacology*
Kinetics
Ligands
Molecular Structure
Morpholines / chemistry*
Morpholines / pharmacology*
Protein Binding
Receptor, Cannabinoid, CB2 / physiology*
Structure-Activity Relationship

Substances

3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione hydrochloride
Cannabinoid Receptor Agonists
Imidazolidines
Ligands
Morpholines
Receptor, Cannabinoid, CB2