Revision with unchanged content. 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.