Synthesis and activity of a potent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids

We report the synthesis of a series of 3-carboxy-, 3-(carboxymethyl)-, 3-(omega-phosphonoalkyl)-1-aminocyclobutane-1-carboxylic acids for evaluation as agonists or antagonists of neurotransmission at excitatory amino acid receptors, particularly N-methyl-D-aspartic acid (NMDA) receptors. The compoun...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-10, Vol.33 (10), p.2905-2915
Main Authors: Allan, Robin D, Hanrahan, Jane R, Hambley, Trevor W, Johnston, Graham A. R, Mewett, Kenneth N, Mitrovic, Ann D
Format: Article
Language:English
Subjects:
activity
agonists
Alicyclic compounds
Alicyclic compounds, terpenoids, prostaglandins, steroids
aminocyclobutane-1,3-dicarboxylic acid
analogs
Animals
Chemistry
Crystallography
Dicarboxylic Acids - chemical synthesis
Dicarboxylic Acids - pharmacology
Dicarboxylic Acids - toxicity
Dose-Response Relationship, Drug
evaluation
Exact sciences and technology
In Vitro Techniques
Mice
Models, Molecular
N-methyl-D-aspartic acid
N-Methylaspartate
Organic chemistry
Organophosphonates - chemical synthesis
Organophosphonates - pharmacology
Organophosphonates - toxicity
Preparations and properties
Rats
receptors
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - drug effects
Structure-Activity Relationship
synthesis
X-Ray Diffraction
Citations: Items that cite this one
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Summary:We report the synthesis of a series of 3-carboxy-, 3-(carboxymethyl)-, 3-(omega-phosphonoalkyl)-1-aminocyclobutane-1-carboxylic acids for evaluation as agonists or antagonists of neurotransmission at excitatory amino acid receptors, particularly N-methyl-D-aspartic acid (NMDA) receptors. The compounds were evaluated as agonists on their ability to depolarize the rat brain cortical wedge preparation or as antagonist of the actions of the selective agonists NMDA, quisqualic acid, and kainic acid. The chain-elongated glutamate derivatives with potential antagonist activity proved to be weak and frequently nonselective antagonists in this assay. The most noteworthy result was that trans isomer 7b was a very potent agonist, approximately 20 times more active than NMDA at NMDA receptors, while the cis isomer was 1/3 as potent as NMDA.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00172a036