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

In this paper, we describe the synthesis of a series of α-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 in...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-01, Vol.41 (3), p.346-357
Main Authors: Ornstein, Paul L, Bleisch, Thomas J, Arnold, M. Brian, Wright, Rebecca A, Johnson, Bryan G, Schoepp, Darryle D
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Excitatory Amino Acid Antagonists - chemistry
Excitatory Amino Acid Antagonists - metabolism
Excitatory Amino Acid Antagonists - pharmacology
Glutamatergic system (aspartate and other excitatory aminoacids)
Glycine - analogs & derivatives
Glycine - chemistry
Glycine - pharmacology
Humans
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Prosencephalon - metabolism
Rats
Receptors, Metabotropic Glutamate - antagonists & inhibitors
Recombinant Proteins - antagonists & inhibitors
Structure-Activity Relationship
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Summary:In this paper, we describe the synthesis of a series of α-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 0.010 μM in the [3H]Glu binding assay, was 52-fold more potent than 2, whose IC50 was 0.47 μM.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970497w