(2S,1‘S,2‘S,3‘R)-2-(2‘-Carboxy-3‘-methylcyclopropyl) Glycine Is a Potent and Selective Metabotropic Group 2 Receptor Agonist with Anxiolytic Properties

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 o...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-08, Vol.45 (17), p.3619-3629
Main Authors: Collado, Iván, Pedregal, Concepción, Mazón, Angel, Espinosa, Juan Félix, Blanco-Urgoiti, Jaime, Schoepp, Darryle D, Wright, Rebecca A, Johnson, Bryan G, Kingston, Ann E
Format: Article
Language:English
Subjects:
Animals
Anti-Anxiety Agents - chemical synthesis
Anti-Anxiety Agents - chemistry
Anti-Anxiety Agents - pharmacology
Biological and medical sciences
Bridged Bicyclo Compounds - chemistry
Bridged Bicyclo Compounds - pharmacology
Cell Line
Cyclopropanes - chemical synthesis
Cyclopropanes - chemistry
Cyclopropanes - pharmacology
Glycine - analogs & derivatives
Glycine - chemical synthesis
Glycine - chemistry
Glycine - pharmacology
Ligands
Medical sciences
Models, Molecular
Neuropharmacology
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Rats
Receptors, Metabotropic Glutamate - agonists
Reflex, Startle - drug effects
Stereoisomerism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0110486