Paul Ornstein - Synthesis and structure-activity relationship studies of novel 2-diarylethyl substituted (2-carboxycycloprop-1-yl)glycines as high-affinity group II metabotropic glutamate receptor ligands.

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      Publication Details (including relevant citation   information):

      Sørensen, Ulrik S, Bleisch, Thomas J, Kingston, Anne E, Wright,   Rebecca A, Johnson, Bryan G, Schoepp, Darryle D, Ornstein, Paul L   Bioorganic & Medicinal Chemistry  2003 11 (2) 197-205

      Abstract: The major excitatory neurotransmitter   in the central nervous system, (S)-glutamic acid , activates both   ionotropic and metabotropic excitatory amino acid receptors. Its   importance in connection to neurological and psychiatric   disorders has directed great attention to the development of   compounds that modulate the effects of this endogenous ligand.   Whereas L-carboxycyclopropylglycine (L-CCG-1) is a potent agonist   at, primarily, group II metabotropic glutamate receptors,   alkylation of at the alpha-carbon notoriously result in group II   mGluR antagonists, of which the most potent compound described so   far, LY341495, displays IC(50) values of 23 and 10 nM at the   group II receptor subtypes mGlu2 and mGlu3, respectively. In this   study we synthesized a series of structural analogues of in which   the xanthyl moiety is replaced by two substituted-phenyl groups.   The pharmacological characterization shows that these novel   compounds have very high affinity for group II mGluRs when tested   as their racemates. The most potent analogues demonstrate K(i)   values in the range of 5-12 nM, being thus comparable to   LY341495.;

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