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histamine H4 receptors ; molecular pharmacology ; recombinant receptors ; adenosine receptors ; cannabinoid receptors
Abstract:
Presented thesis describes the development of cell lines, overexpressing adenosine A2A, cannabinoid CB1 and CB2 and histamine H4 receptors. Derived cellular models supplemented available tools to investigate the molecular pharmacology of seven-transmembrane receptors.Within the study, an influence of transfection/transduction method and labeling of receptor with fluorescent protein, on ligand binding parameters was evaluated for adenosine A2A and histamine H4 receptors.Cell lines obtained in current work were additionally used to test 61 derivatives of dialkyl-pyrimidopurinediones for their activity towards the family of adenosine receptors. In the considered group of structures, active compounds were identified (with Ki values in nanomolar and submicromolar concentration range), representing various selectivity to particular receptor subtypes. The obtained results enabled the identification of crucial structural elements of tested compounds, necessary for achievement of high affinity to adenosine receptors.Experiments carried out within the study allowed for confirmation of agonistic activity of Δ9-THC at GPR18 orphan receptor. Moreover, β-arrestin recruitment assay at GPR18 receptor, in connection with CB1R and CB2R radioligand binding assays, developed within the presented thesis, were used for the characterization of 41 derivatives of imidazothiazolone, imidazothiazinone an ; d imidazo-thiazepinone as a potential ligands of cannabinoid receptors subtypes and GPR18 orphan receptor.