Phenotypic screening of cannabinoid receptor 2 ligands shows different sensitivity to genotype.
The Cannabinoid Receptor 2 (CB2R) is a G protein-coupled receptor (GPCR) investigated intensively as therapeutic target, however no drug has reached the market yet. We investigated personal differences in CB2R drug responses using a label-free whole-cell assay (xCELLigence) combined with cell lines (Lymphoblastoid Cell Lines) from individuals with varying CB2R genotypes. Responses to agonists, partial agonists and antagonists of various chemical classes were characterized. Endogenous cannabinoids such as 2-AG induced cellular effects vastly different from all synthetic cannabinoids, especially in their time-profile. Secondly, the Q63R polymorphism affected CB2R responses in general. Agonists and especially partial agonists showed higher efficacy in a Q63R minor homozygote versus other genotypes. Non-classical cannabinoid CP55940 showed the most pronounced personal effects with highly reduced potency and efficacy in this genotype. Contrarily, aminoalkylindole compounds showed less individual differences. In conclusion, a label-free whole-cell assay combined with personal cell lines is a promising vehicle to investigate personal differences in drug response originating from genetic variation in GPCRs. Such phenotypic screening allows early identification of compounds prone to personal differences ('precision medicine') or more suited as drugs for the general population.
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Julia M
JM
Hillger
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Beau
B
le Roy
Division of Toxicology, LACDR, Leiden University, The Netherlands.
Zi
Z
Wang
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Thea
T
Mulder-Krieger
Department of Biological Psychology, Vrije Universiteit Amsterdam, The Netherlands.
Dorret I
DI
Boomsma
Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands.
P Eline
PE
Slagboom
Division of Toxicology, LACDR, Leiden University, The Netherlands.
Erik H J
EHJ
Danen
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Adriaan P
AP
IJzerman
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands. Electronic address: l.h.heitman@lacdr.leidenuniv.nl.
Laura H
LH
Heitman
D002186:Cannabinoids / Q000378:metabolism*; D002478:Cells, Cultured; D005838:Genotype; D006801:Humans; D008024:Ligands; D010641:Phenotype; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
D002186:Cannabinoids; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2
2-AG (PubMed CID: 5282280); AEA (PubMed CID: 5281969); AM251 (PubMed CID: 2125); AM630 (PubMed CID: 4302963); BAY59-3074 (PubMed CID: 10479060); CP55940 (PubMed CID: 10479060); Cannabinoid receptor 2; GW405833 (PubMed CID: 46916568); JWH133 (PubMed CID: 6918505); Label-free; Lymphoblastoid cell lines; Precision medicine; Single Nucleotide Polymorphism; WIN55212-2 (PubMed CID: 5311501)