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, Ar

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• 作者：Paul L. Ornstein ; Thomas J. Bleisch ; M. Brian Arnold ; Rebecca A. Wright ; Bryan G. Johnson ; and Darryle D. Schoepp
• 刊名：Journal of Medicinal Chemistry
• 出版年：1998
• 出版时间：January 29, 1998
• 年：1998
• 卷：41
• 期：3
• 页码：346 - 357
• 全文大小：194K
• 年卷期：v.41,no.3(January 29, 1998)
• ISSN：1520-4804

文摘

In this paper, we describe the synthesis of a series ofG SRC="/images/gifchars/alpha.gif" BORDER=0>-substituted analogues of the potentand selective group II metabotropic glutamate receptor (mGluR) agonist(1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of asubstituent on the amino acid carbonconverted the agonist 2 into an antagonist. All of thecompounds were prepared and tested asa series of four isomers, i.e., two racemic diastereomers. Weexplored alkyl substitution, bothnormal and terminally branched; phenylalkyl and diphenylalkylsubstitution; and a variety ofaromatic and carbocyclic surrogates for phenyl. Affinity for groupII mGluRs was measuredusing [³H]glutamic acid (Glu) binding in ratforebrain membranes. Antagonist activity wasconfirmed for these compounds by measuring their ability to antagonize(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition offorskolin-stimulated cyclic-AMP in RGTcells transfected with human mGluR2 and mGluR3. We found thatwhile alkyl substitutionprovided no increase in affinity relative to 2, phenylethyland diphenylethyl substitution, asin 105 and 109, respectively, were quitebeneficial. The affinity of 109 was furtherenhancedwhen the two aromatic rings were joined by an oxygen or sulfur atom toform the tricyclicxanthylmethyl and thioxanthylmethyl amino acids 113 and114, respectively. Amino acid113,with an IC₅₀ of 0.010 ges/entities/mgr.gif">M in the[³H]Glu binding assay, was 52-fold more potent than2, whoseIC₅₀ was 0.47 ges/entities/mgr.gif">M.