Source:http://linkedlifedata.com/resource/pubmed/id/10934211
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
43
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pubmed:dateCreated |
2000-11-24
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pubmed:abstractText |
We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel mGluR5 radioligand [(3)H]2-methyl-6-(3-methoxyphenyl)ethynyl pyridine (M-MPEP), a close analog of MPEP. Replacement of Ala-810 in transmembrane (TM) VII or Pro-655 and Ser-658 in TMIII with the homologous residues of hmGluR1 abolished radioligand binding. In contrast, the reciprocal hmGluR1 mutant bearing these three residues of hmGluR5 showed high affinity for [(3)H]M-MPEP. Radioligand binding to these mutants was also inhibited by 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), a structurally unrelated non-competitive mGluR1 antagonist previously shown to interact with residues Thr-815 and Ala-818 in TMVII of hmGluR1. These results indicate that MPEP and CPCCOEt bind to overlapping binding pockets in the TM region of group I mGluRs but interact with different non-conserved residues.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/6-methyl-2-(phenylethynyl)pyridine,
http://linkedlifedata.com/resource/pubmed/chemical/7-(hydroxyimino)cyclopropan(b)chrome...,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/Excitatory Amino Acid Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Metabotropic Glutamate
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:CambriaAA,
pubmed-author:CarrollFF,
pubmed-author:FloersheimPP,
pubmed-author:FlorP JPJ,
pubmed-author:GaspariniFF,
pubmed-author:HeinrichMM,
pubmed-author:KuhnRR,
pubmed-author:LinF XFX,
pubmed-author:LitschigSS,
pubmed-author:PaganoAA,
pubmed-author:PrezèauLL,
pubmed-author:RueggDD,
pubmed-author:StierlinCC,
pubmed-author:StoehrNN,
pubmed-author:VranesicII
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pubmed:issnType |
Print
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pubmed:day |
27
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pubmed:volume |
275
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
33750-8
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pubmed:dateRevised |
2005-11-17
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pubmed:meshHeading |
pubmed-meshheading:10934211-Amino Acid Sequence,
pubmed-meshheading:10934211-Animals,
pubmed-meshheading:10934211-Binding Sites,
pubmed-meshheading:10934211-CHO Cells,
pubmed-meshheading:10934211-COS Cells,
pubmed-meshheading:10934211-Chromones,
pubmed-meshheading:10934211-Cricetinae,
pubmed-meshheading:10934211-Excitatory Amino Acid Antagonists,
pubmed-meshheading:10934211-Models, Molecular,
pubmed-meshheading:10934211-Molecular Sequence Data,
pubmed-meshheading:10934211-Pyridines,
pubmed-meshheading:10934211-Rats,
pubmed-meshheading:10934211-Receptors, Metabotropic Glutamate,
pubmed-meshheading:10934211-Structure-Activity Relationship
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pubmed:year |
2000
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pubmed:articleTitle |
The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.
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pubmed:affiliation |
Novartis Pharma AG, Nervous System Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland.
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pubmed:publicationType |
Journal Article
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