3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2)

• Published in: Bioorganic & medicinal chemistry letters 2005-05, Vol.15 (9), p.2389-2393
• Main Authors: Cube, Rowena V., Vernier, Jean-Michel, Hutchinson, John H., Gardner, Michael F., James, Joyce K., Rowe, Blake A., Schaffhauser, Herve, Daggett, Lorrie, Pinkerton, Anthony B.
• Format: Article
• Language: English
• Subjects: Allosteric modulator; Allosteric Regulation; Animals; Biological and medical sciences; Brain - drug effects; Brain - physiology; Butanes - chemical synthesis; Butanes - pharmacokinetics; Butanes - pharmacology; Coumarin; Glutamate; Glutamatergic system (aspartate and other excitatory aminoacids); Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Kinetics; Medical sciences; mGluR2; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phenyl Ethers; Potentiator; Propionates - chemical synthesis; Propionates - pharmacokinetics; Propionates - pharmacology; Rats; Receptors, Metabotropic Glutamate - drug effects; Receptors, Metabotropic Glutamate - physiology; Structure-Activity Relationship; Tetrazole
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.02.078

We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC 50 = 1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk ip, brain level of 5700 nM). We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure–activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC 50 = 1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk ip, brain level of 5700 nM).