Synthesis and Metabotropic Glutamate Receptor Activity of S-Oxidized Variants of (-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: Identification of Potent, Selective, and Orally Bioavailable

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• 作者：James A. Monn ; Steven M. Massey ; Matthew J. Valli ; Steven S. Henry ; Gregory A. Stephenson ; Mark Bures ; Marc Hé ; rin ; John Catlow ; Deborah Giera ; Rebecca A. Wright ; Bryan G. Johnson ; Sherri L. And
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 25, 2007
• 年：2007
• 卷：50
• 期：2
• 页码：233 - 240
• 全文大小：250K
• 年卷期：v.50,no.2(January 25, 2007)
• ISSN：1520-4804

文摘

(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selectiveagonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing researchprogram, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and(-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3receptor antagonist ³H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (³H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonistsin cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, tomGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 inrats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonistpotency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulationsin a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.