Abstract
An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago-potentiator ADX-47273. This effort identified key substituents in the 3-position of oxadiazole that engendered either mGluR5 ago-potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.