Discovery of Novel, Potent Metabotropic Glutamate Receptor 5 Allosteric Antagonists

Metabotropic glutamate receptors (mGluR) belong to the G-protein-coupled receptor (GPCR) family and have been divided in three groups. mGluR1 and mGluR5 belong to Group I which couple to phospholipase C and their activation leads to intracellular calcium-ion mobilization. The therapeutic potential of metabotropic glutamate receptor 5 (mGluR5) as a drug target, has recently been explored and expanded. It is considered that mGluR5 receptor antagonists have treatment potential for CNS disorders. Negative allosteric modulators (NAMs) of mGluR5 receptor have several important advantages over orthosteric antagonists, including increased subtype selectivity and much better brain penetration. We have recently identified a series of 6-bromo and 6-chloro pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amides as novel, potent and selective mGluR5 negative allosteric modulators. The synthesis of a new mGluR5 negative allosteric modulators and the stucture – activity relationships is presented