Ligand Binding in the Transmembrane Region of Metabotropic Glutamate Receptors

Group I metabotropic glutamate receptors (mGluRs) play an important role in the treatment of numerous neurodegenerative, cognitive and psychiatric dis­orders. How can we identify exogenous ligands mediating the effects of mGluRs? How do these ligands affect the receptor? The author Tobias Noeske presents the establishment of strategies for the identification and optimization of molecules acting as non-competitive anta­gonists of group I mGluRs. These strategies ensure high diversity in the identi­fied chemotypes not resembling original reference molecules ("scaffold-hop­ping"). The detection of new scaffolds, in turn, is divided into two ap­proa­ches: First the development of pharmacological assays to screen com­pounds at a certain target for their bioactivity, and second the evaluation of com­pu­ter aided methods for the identification of virtual hits to be screened on the pharmacological assays. Promising molecules were optimized regarding bio­activity and selectivity, their binding mode investigated and, fi­nally, com­pared to existing lead compounds. This book addresses scientists in academia and industry working in early stage drug discovery, predominantly in computer aided drug design.