Paul Ornstein - 2-Substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 1. Effects of alkyl, arylalkyl, and diarylalkyl substitution

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      Publication Details (including relevant citation   information):

      Ornstein, Paul L., Bleisch, Thomas J., Arnold, M. Brian, Wright,   Rebecca A., Johnson, Bryan G., Schoepp, Darryle D. Journal of   Medicinal Chemistry 1998 41 (3)   346-357

      Abstract: In this paper, we describe the   synthesis of a series of alpha-substituted analogues of the   potent and selective group II metabotropic glutamate receptor   (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG   1). Incorporation of a substituent on the amino acid carbon   converted the agonist 2 into an antagonist. All of the compounds   were prepared and tested as a series of four isomers, i.e., two   racemic diastereomers. We explored alkyl substitution, both   normal and terminally branched; phenylalkyl and diphenylalkyl   substitution; and a variety of aromatic and carbocyclic   surrogates for phenyl. Affinity for group II mGluRs was measured   Using (3H)glutamic acid (Glu) binding in rat forebrain membranes.   Antagonist activity was confirmed for these compounds by   measuring their ability to antagonize   (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced   inhibition of forskolin-stimulated cyclic-AMP in RGT cells   transfected with human mGluR2 and mGluR3. We found that while   alkyl substitution provided no increase in affinity relative to   2, phenylethyl and diphenylethyl substitution, as in 105 and 109,   respectively, were quite beneficial. The affinity of 109 was   further enhanced when the two aromatic rings were joined by an   oxygen or sulfur atom to form the tricyclic xanthylmethyl and   thioxanthylmethyl amino acids 113 and 114, respectively. Amino   acid 113, with an IC50 of 0.010muM in the (3H)Glu binding assay,   was 52-fold more potent than 2, whose IC50 was 0.47 muM.

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