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Research-GPCRs |
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G-protein coupled receptors are one of the major drug targets in the human genome and consequently one of the main research topics within the DDC. Currently, a lot of attention is given to histamine and chemokine receptors. Investigations within the group of Leurs c.s. focus specifically on the receptor ligand interactions in order to discover new small molecules targeting the specific GPCR of interest. A multidisciplinary approach, combining computational chemistry, organic chemistry, molecular pharmacology and molecular biology is applied to develop potent and specific ligands for the GPCR of interest. In the past the group has been successfully introduced a variety of selected ligands, that are currently used worldwide. Selected publications Ratnala VR, Swarts HG, VanOostrum J, Leurs R, DeGroot HJ, Bakker RA, DeGrip WJ Large-scale overproduction, functional purification and ligand affinities of the His-tagged human histamine H1 receptor. Eur J Biochem, 271 (2004) pp.:2636-46. Kitbunnadaj R, Zuiderveld OP, Christophe B, Hulscher S, Menge WM, Gelens E, Snip E, Bakker RA, Celanire S, Gillard M, Talaga P, Timmerman H, Leurs R Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H3 receptor agonist. J Med Chem, 47 (2004) pp.:2414-7. Bakker RA, Weiner DM, ter Laak T, Beuming T, Zuiderveld OP, Edelbroek M, Hacksell U, Timmerman H, Brann MR, Leurs R 8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist. Mol Pharmacol, 65 (2004) pp.:538-49. Govoni M, Bakker RA, van de Wetering I, Smit MJ, Menge WM, Timmerman H, Elz S, Schunack W, Leurs R Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists. J Med Chem, 46 (2003) pp.:5812-24. Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, Lutz M, Spek AL, Cavoy E, Deltent MF, Menge WM, Timmerman H, Leurs R Synthesis and structure-activity relationships of conformationally constrained histamine H3 receptor agonists. J Med Chem, 46 (2003) pp.:5445-57. Hashimoto T, Harusawa S, Araki L, Zuiderveld OP, Smit MJ, Imazu T, Takashima S, Yamamoto Y, Sakamoto Y, Kurihara T, Leurs R, Bakker RA, Yamatodani A A selective human H4-receptor agonist: [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine. J Med Chem, 46 (2003) pp.:3162-5. Casarosa P, Menge WM, Minisini R, Otto C, van Heteren J, Jongejan A, Timmerman H, Moepps B, Kirchhoff F, Mertens T, Smit MJ, Leurs R Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J Biol Chem, 278 (2003) pp.:5172-8. De Esch IJ, Mills JE, Perkins TD, Romeo G, Hoffmann M, Wieland K, Leurs R, Menge WM, Nederkoorn PH, Dean PM, Timmerman H Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE. J Med Chem, 44 (2001) pp.:1666-74. |