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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
1998-4-16
|
| pubmed:abstractText |
(RS)-2-Amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid (Bu-HIBO, 6) has previously been shown to be an agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors and an inhibitor of CaCl2-dependent [3H]-(S)-glutamic acid binding (J. Med. Chem. 1992, 35, 3512-3519). To elucidate the pharmacological significance of this latter binding affinity, which is also shown by quisqualic acid (3) but not by AMPA, we have now resolved Bu-HIBO via diastereomeric salt formation using the diprotected Bu-HIBO derivative 11 and the enantiomers of 1-phenylethylamine (PEA). The absolute stereochemistry of (S)-Bu-HIBO (7) (ee = 99.0%) and (R)-Bu-HIBO (8) (ee > 99.6%) were established by an X-ray crystallographic analysis of compound 15, a salt of (R)-PEA, and diprotected 8. Circular dichroism spectra of 7 and 8 were recorded. Whereas 7 (IC50 = 0.64 microM) and 8 (IC50 = 0.57 microM) were equipotent as inhibitors of CaCl2-dependent [3H]-(S)-glutamic acid binding, neither enantiomer showed significant affinity for the synaptosomal (S)-glutamic acid uptake system(s). AMPA receptor affinity (IC50 = 0.48 microM) and agonism (EC50 = 17 microM) were shown to reside exclusively in the S-enantiomer, 7. Compounds 7 and 8 did not interact detectably with kainic acid or N-methyl-D-aspartic acid (NMDA) receptor sites. Neither 7 nor 8 affected the function of the metabotropic (S)-glutamic acid receptors mGlu2 and mGlu4a, expressed in CHO cells. Compound 8 was shown also to be inactive at mGlu1 alpha, whereas 7 was determined to be a moderately potent antagonist at mGlu1 alpha (Ki = 110 microM) and mGlu5a (Ki = 97 microM). Using the rat cortical wedge preparation, the AMPA receptor agonist effect of 7 was markedly potentiated by coadministration of 8 at 21 degrees C, but not at 2-4 degrees C. These observations together indicate that the potentiation of the AMPA receptor agonism of 7 by 8 is not mediated by metabotropic (S)-glutamate receptors but rather by the CaCl2-dependent (S)-glutamic acid binding system, which shows the characteristics of a transport mechanism. After intravenous administration in mice, 7 (ED50 = 44 mumol/kg) was slightly more potent than AMPA (1) (ED50 = 55 mumol/kg) and twice as potent as Bu-HIBO (6) (ED50 = 94 mumol/kg) as a convulsant, whereas 8 was inactive. After subcutaneous administration in mice, Bu-HIBO (ED50 = 110 mumol/kg) was twice as potent as AMPA (ED50 = 220 mumol/kg) as a convulsant. Since 7 and Bu-HIBO (EC50 = 37 microM) are much weaker than AMPA (EC50 = 3.5 microM) as AMPA receptor agonists in vitro, the presence of a butyl group in the molecules of Bu-HIBO and 7 seems to facilitate the penetration of these compounds through the blood-brain barrier.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Anticonvulsants,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Chloride,
http://linkedlifedata.com/resource/pubmed/chemical/Excitatory Amino Acid Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Excitatory Amino Acid Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Isoxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, AMPA,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glutamate,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Metabotropic Glutamate,
http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor 2,
http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor 4,
http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor...
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
12
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| pubmed:volume |
41
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
930-9
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:9526567-Alanine,
pubmed-meshheading:9526567-Animals,
pubmed-meshheading:9526567-Anticonvulsants,
pubmed-meshheading:9526567-Brain,
pubmed-meshheading:9526567-CHO Cells,
pubmed-meshheading:9526567-Calcium Chloride,
pubmed-meshheading:9526567-Chromatography, High Pressure Liquid,
pubmed-meshheading:9526567-Cricetinae,
pubmed-meshheading:9526567-Crystallography, X-Ray,
pubmed-meshheading:9526567-Electrophysiology,
pubmed-meshheading:9526567-Excitatory Amino Acid Agonists,
pubmed-meshheading:9526567-Excitatory Amino Acid Antagonists,
pubmed-meshheading:9526567-Isoxazoles,
pubmed-meshheading:9526567-Male,
pubmed-meshheading:9526567-Mice,
pubmed-meshheading:9526567-Molecular Conformation,
pubmed-meshheading:9526567-Rats,
pubmed-meshheading:9526567-Rats, Sprague-Dawley,
pubmed-meshheading:9526567-Receptors, AMPA,
pubmed-meshheading:9526567-Receptors, Glutamate,
pubmed-meshheading:9526567-Receptors, Metabotropic Glutamate,
pubmed-meshheading:9526567-Stereoisomerism
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| pubmed:year |
1998
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| pubmed:articleTitle |
Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid.
|
| pubmed:affiliation |
PharmaBiotec Research Center, Department of Medicinal Chemistry, Royal Danish School of Pharmacy, 2 Universitetsparken, Copenhagen, Denmark.
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| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
|