Linked Life Data

11087567

Source:http://linkedlifedata.com/resource/pubmed/id/11087567

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2000-12-4
pubmed:abstractText
Racemic CPCCOEt ((1aRS,7aRS)-2-hydroxyimino-1a, 2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester, (+/-)-1) derivatives have been shown to be subtype-selective metabotropic glutamate (mGlu) 1 receptor antagonists (Annoura et al. Bioorg. Med. Chem. Lett. 1996, 6, 763-766). The optical isomers of (+/-)-1 have been separated by chromatography on a chiral stationary phase. The absolute configuration at the C-1a and C-7a positions was determined using X-ray crystallography of an amide derivative with the methyl ester of L-phenylalanine (L-PheOMe) ((+)-6). In a phosphoinositol (PI) turnover assay at the cloned human mGlu1b receptor, (-)-1 and the new amide derivatives (-)-5 and (-)-6, all of which have (1aS,7aS)-stereochemistry on the chromane ring system, showed IC(50) values of 1.5, 0.43, and 0.93 microM, respectively. In contrast, (+)-1 and the new amide derivatives (+)-5 and (+)-6were found to be inactive up to a concentration of 30 microM indicating a selectivity for the (-)-enantiomers of at least 70-fold. In a previous study (Litschig et al. Mol. Pharmacol. 1999, 55, 453-461) we demonstrated using site-directed mutagenesis that the interaction site of (+/-)-1 is located in the transmembrane (TM) domain of hmGlu1b. To suggest a plausible binding mode of (-)-1, we have built a molecular mechanics model of the putative seven TM domain of hmGlu1 based on the alpha-carbon template of the TM helices of rhodopsin. A receptor docking hypothesis suggests that the OH of T815 (TMVII) comes in close contact with the oxime OH of (-)-1 and (-)-5, whereas no such close interactions could be demonstrated by docking of (+)-1.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4428-36
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed:year
2000
pubmed:articleTitle
Chiral resolution, pharmacological characterization, and receptor docking of the noncompetitive mGlu1 receptor antagonist (+/-)-2-hydroxyimino- 1a, 2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester.
pubmed:affiliation
Nervous System Research and Core Technologies, Novartis Pharma AG, CH-4002 Basel, Switzerland.
pubmed:publicationType
Journal Article