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. 2. Effects of aromatic substitution, pharmacological characterization, and bioav...

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      Ornstein, Paul L., Bleisch, Thomas J., Arnold, M. Brian, Kennedy,   Joseph H., Wright, Rebecca A., Johnson, Bryan G., Tizzano, Joseph   P., Helton, David R., Kallman, Mary Jeanne, Schoepp, Darryle D.   Journal of Medicinal Chemistry 1998  41 (3) 358-378

      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. On the basis of the improvement in   affinity realized for the alpha-phenylethyl analogue 3, in this   paper we explored the effects of substitution on the aromatic   ring as a strategy to increase the affinity of these compounds   for group II mGluRs. 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. Meta substitution on   the aromatic ring of 3 with a variety of substituents, both   electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl,   phenoxy) and electron withdrawing (e.g., fluorine, chlorine,   bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold   increases in affinity. Substitution with p-fluorine, as in 97   (IC50 = 0.022 +- 0.002), was the exception. Here, a greater   increase in affinity was realized than for either the ortho- or   meta-substituted analogues; 97 was the most potent compound   resulting from monosubstitution of the aromatic. At best, only   modest increases in affinity were realized for certain compounds   bearing either two chlorines or two fluorines, and two methoxy   groups gave no improvement in affinity (all examined in a variety   of substitution patterns). Three amino acids, 4, 5, and 104, were   resolved into their four constituent isomers, and affinity and   functional activity for group II mGluRs was found to reside   solely in the SSS-isomers of each, consistent with 1. With an   IC50 = 2.9 +- 0.6 nM, the resolved xanthylmethyl compound 168 was   the most potent compound from this SAR. Amino acid 168   demonstrated high plasma levels following intraperitoneal (ip)   administration and readily penetrated into the brain. This   compound, however, had only limited (apprx5%) oral   bioavailability. Systemic administration of 168 protected mice   from limbic seizures produced by the mGluR agonist   3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (ip, 60 min   preinjection). Thus, 168 represents a valuable tool to study the   role of group II mGluRs in disease.

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