Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-Thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators

We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC50 = 340 nM), which showed improved brain penetration over the initial lead.