Dysfunctional glutamatergic transmission contributes to the pathology of many diseases including schizophrenia, anxiety, and drug addiction. One approach to address this condition is modulation of Group II mGluRs by small molecules. Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are found pre- and postsynaptically and couple to Gi and Go-proteins to negatively regulate the activity of adenylyl cyclase and also function as glutamate autoreceptors to modulate presynaptic glutamate release. We have an ongoing program focused on designing and optimizing small molecule modulators of Group II mGluRs as starting points for further therapeutic development and in vivo evaluation. In the present study, we sought to develop modulators possessing varying degrees of selectivity between mGluR2 and mGluR3. In the course of our efforts, we discovered both mGluR2 selective and balanced mGluR2/mGluR3 positive allosteric modulators (PAMs) having comparable PAM activity at both receptors. Our strategy involved the identification of several key fragments from a series of mGluR2 PAM scaffolds and combination of these fragments in a matrix approach to generate a focused library of new structures. In addition to the unprecedented selectivity, these PAMs have favorable ADME/T and pharmacokinetic properties and represent systemically active mGluR PAMs to be further characterized in relevant tests, including models of cocaine dependence.

Development of drug-like small molecule group II metabotropic glutamate receptor (mGluR) positive allosteric modulators (PAMs) having differential selectivity: Discovery of mGluR PAMs possessing either selective or balanced mGluR2/mGluR3 activity

243rd National Meeting (2012)

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