mGluR5 positive allosteric modulators

The mGluR(5) subtype of metabotropic glutamate receptor (mGluR) plays an important role in the modulation of neuronal excitability and synaptic transmission in a number of brain circuits. These slow synaptic responses involving mGluR(5) are mediated by activation of second messenger systems and intracellular signaling pathways. Recent advances suggest that selective activation of mGIuR. may have exciting potential for the treatment of multiple psychiatric and neurological disorders. Thus, it is important to develop mGluR(5)-selective activators as useful tools to study the roles of mGluR(5) in diseases or as novel therapeutic agents. Several useful mGluR(5) orthosteric agonists have been discovered and, more recently, several families of mGluR(5) positive allosteric modulators (PAMs) were identified. The mGluR(5) PAMs do not directly activate the receptor, but rather enhance its sensitivity to agonists by acting through binding to the allosteric sites in the seven-transmembrane-spanning domains. Physiological and behavioral studies demonstrate that mGIuR. PAMs potentiate mGluR(5)-mediated responses in brain slices and display efficacy in animal models that predict for antipsychotic effects. The unique pharmacological properties of mGluR(5) PAMs enable them to be used as novel research tools or potential therapeutic agents with distinct advantages over classic orthosteric agonists.