Abstract
The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.
MeSH terms
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Animals
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Anti-Anxiety Agents / chemical synthesis*
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Anti-Anxiety Agents / chemistry
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Anti-Anxiety Agents / pharmacology
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacology
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Cell Line
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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Glycine / analogs & derivatives
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Glycine / chemical synthesis*
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Glycine / chemistry
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Glycine / pharmacology
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Ligands
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Models, Molecular
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Rats
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Receptors, Metabotropic Glutamate / agonists*
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Reflex, Startle / drug effects
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Stereoisomerism
Substances
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2-(2'-carboxy-3'-methylcyclopropyl)glycine
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Anti-Anxiety Agents
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Bridged Bicyclo Compounds
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Cyclopropanes
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Ligands
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor 2
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eglumetad
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Glycine