| Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue. | |
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MedLine Citation:
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PMID: 12585893 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid). |
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Authors:
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Lennart Bunch; Tommy Liljefors; Jeremy R Greenwood; Karla Frydenvang; Hans Bräuner-Osborne; Povl Krogsgaard-Larsen; Ulf Madsen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of organic chemistry Volume: 68 ISSN: 0022-3263 ISO Abbreviation: J. Org. Chem. Publication Date: 2003 Feb |
Date Detail:
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Created Date: 2003-02-14 Completed Date: 2003-10-20 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985193R Medline TA: J Org Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1489-95 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. lebu@dfh.dk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aza Compounds
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chemical synthesis*,
pharmacology* Dicarboxylic Acids / chemical synthesis*, pharmacology* Glutamic Acid* / analogs & derivatives, chemistry, pharmacology Inhibitory Concentration 50 Kainic Acid / pharmacology Magnetic Resonance Spectroscopy Molecular Conformation Molecular Mimicry Molecular Structure Norbornanes / chemical synthesis*, pharmacology* Receptors, Glutamate / chemistry*, metabolism* Stereoisomerism Structure-Activity Relationship alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/2-azanorbornane-3-exo,5-endo-dicarboxylic acid; 0/Aza Compounds; 0/Dicarboxylic Acids; 0/Norbornanes; 0/Receptors, Glutamate; 487-79-6/Kainic Acid; 56-86-0/Glutamic Acid; 77521-29-0/alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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