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Phenotypic screening of cannabinoid receptor 2 ligands shows different sensitivity to genotype.

Authors
  • Hillger, Julia M1
  • le Roy, Beau1
  • Wang, Zi2
  • Mulder-Krieger, Thea1
  • Boomsma, Dorret I3
  • Slagboom, P Eline4
  • Danen, Erik H J2
  • IJzerman, Adriaan P1
  • Heitman, Laura H5
  • 1 Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands. , (Netherlands)
  • 2 Division of Toxicology, LACDR, Leiden University, The Netherlands. , (Netherlands)
  • 3 Department of Biological Psychology, Vrije Universiteit Amsterdam, The Netherlands. , (Netherlands)
  • 4 Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands. , (Netherlands)
  • 5 Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands. Electronic address: [email protected] , (Netherlands)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Apr 15, 2017
Volume
130
Pages
60–70
Identifiers
DOI: 10.1016/j.bcp.2017.01.014
PMID: 28159624
Source
Medline
Keywords
License
Unknown

Abstract

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.

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