2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.

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