Synthesis, Structure−Activity Relationship, and Receptor Pharmacology of a New Series of Quinoline Derivatives Acting as Selective, Noncompetitive mGlu1 Antagonists
| Autor: | Dominique Jean-Pierre Mabire, Alain Philippe Poncelet, Anne Simone Josephine Lesage, Ludy van Beijsterveldt, François Paul Bischoff, Ria Wouters, Christophe Adelinet, Yvan Rene Simonnet, Sophie Coupa, Marc Venet |
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| Rok vydání: | 2005 |
| Předmět: |
Intracellular Fluid
Stereochemistry Biological Availability CHO Cells In Vitro Techniques Receptors Metabotropic Glutamate Structure-Activity Relationship chemistry.chemical_compound Cricetulus Cell Line Tumor Cricetinae Drug Discovery Animals Humans Structure–activity relationship Receptor IC50 Chemistry Quinoline Antagonist Stereoisomerism Rats Metabotropic receptor Biochemistry Microsomes Liver Quinolines Molecular Medicine Calcium Signal transduction Lead compound Half-Life Signal Transduction |
| Zdroj: | Journal of Medicinal Chemistry. 48:2134-2153 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 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 mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 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. |
| Databáze: | OpenAIRE |
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