The traditional medical treatment paradigm focuses on prescribing one drug to treat all patients with a specific disease or condition, so called ‘one-size-fits-all’. However, it has been shown... Show moreThe traditional medical treatment paradigm focuses on prescribing one drug to treat all patients with a specific disease or condition, so called ‘one-size-fits-all’. However, it has been shown increasingly that differences between persons, such as in lifestyle or genes, can change both the course of a disease and effect of a drug. In order to adapt medical treatment and drug development to that, a concept know as precision medicine, it is essential to study which and how genetic differences affect drug response. This thesis describes the study of the influences of genetic variation on a specific class of drug targets, the G protein-coupled receptors (GPCRs).Altogether a novel cellular approach towards studying genetic effects on GPCR function has been explored and detailed throughout this thesis. Several GPCRs and different types of genetic variations were investigated, demonstrating together that personal cell lines in combination with label-free technology are an appropriate tool to enable GPCR pharmacogenetic studies. Incorporating aspects such as genetic variation in drug targets, representative model systems and appropriate assay technology are important factors for advancing GPCR drug discovery. The data presented in this thesis contributes towards the progress of applying precision medicine concepts to this class of drug targets. Show less
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... Show moreThe 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. Show less
