Schizophrenia is a disease in which the function of the NMDA receptor is compromised. The disease manifests a number of complex behavior disorders including deficits in associative learning, working memory, behavioral flexibility, and attention. Activation of metabotropic glutamate receptor 5 (mGlu5) is known to increase the function of NMDA and is a promising non-dopamine based target for potential therapeutic intervention. In an investigation of mGlu5 positive allosteric modulators (PAMs) derived from an HTS screen, we have identified a series of monocyclic ethers with various heterocyclic core structures bearing an amide substituent and an aliphatic ether linkage. Strategies to improve physicochemical properties, functional potency, and selectivity will be presented.

Investigation of monocyclic ethers as positive allosteric modulators of mGlu5

244th National Meeting (2012)

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