Source:http://linkedlifedata.com/resource/pubmed/id/18056795
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2008-2-22
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| pubmed:abstractText |
Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.
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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/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Metabotropic Glutamate,
http://linkedlifedata.com/resource/pubmed/chemical/Valine,
http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor...
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
1521-0111
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
73
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
909-18
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| pubmed:meshHeading |
pubmed-meshheading:18056795-Allosteric Regulation,
pubmed-meshheading:18056795-Allosteric Site,
pubmed-meshheading:18056795-Amino Acid Sequence,
pubmed-meshheading:18056795-Amino Acid Substitution,
pubmed-meshheading:18056795-Animals,
pubmed-meshheading:18056795-Astrocytes,
pubmed-meshheading:18056795-Benzamides,
pubmed-meshheading:18056795-Calcium,
pubmed-meshheading:18056795-Cell Culture Techniques,
pubmed-meshheading:18056795-Cell Line,
pubmed-meshheading:18056795-Cells, Cultured,
pubmed-meshheading:18056795-Cerebral Cortex,
pubmed-meshheading:18056795-Cricetinae,
pubmed-meshheading:18056795-Dose-Response Relationship, Drug,
pubmed-meshheading:18056795-Humans,
pubmed-meshheading:18056795-Kidney,
pubmed-meshheading:18056795-Ligands,
pubmed-meshheading:18056795-Molecular Sequence Data,
pubmed-meshheading:18056795-Molecular Structure,
pubmed-meshheading:18056795-Protein Structure, Tertiary,
pubmed-meshheading:18056795-Radioligand Assay,
pubmed-meshheading:18056795-Rats,
pubmed-meshheading:18056795-Receptors, Metabotropic Glutamate,
pubmed-meshheading:18056795-Sequence Homology, Amino Acid,
pubmed-meshheading:18056795-Transfection,
pubmed-meshheading:18056795-Valine
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| pubmed:year |
2008
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| pubmed:articleTitle |
N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors.
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| pubmed:affiliation |
Department of Pharmacology, Vanderbilt University Medical Center, 23rd Avenue South at Pierce, 417-D Preston Research Building, Nashville, TN 37232-6600, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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