Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlul antagonists. We first identified cis-10 as a fairly potent mGlul antagonist (IC50 = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlul receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlul receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.