Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlul 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 (IC sub(50) = 20 nM) in a cell-based signal transduction a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-03, Vol.48 (6), p.2134-2153
Main Authors: MABIRE, Dominique, COUPA, Sophie, ADELINET, Christophe, PONCELET, Alain, SIMONNET, Yvan, VENET, Marc, WOUTERS, Ria, LESAGE, Anne S. J, VAN BEIJSTERVELDT, Ludy, BISCHOFF, Francois
Format: Article
Language:English
Subjects:
Biological and medical sciences
Glutamatergic system (aspartate and other excitatory aminoacids)
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
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Summary: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 (IC sub(50) = 20 nM) in a cell-based signal transduction assay on the rat mG1u1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mG1u1 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049499o