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):

      Sorensen, 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 (1), 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, 2) is a potent   agonist at, primarily, group II metabotropic glutamate receptors,   alkylation of 2 at the alpha-carbon notoriously result in group   II mGluR antagonists, of which the most potent compound described   so far, LY341495 (12), displays IC50 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 12   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   Ki values in the range of 5-12 nM, being thus comparable to   LY341495 (12).

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