| Structural determinants of 4-chloro-m-cresol required for activation of ryanodine receptor type 1. | |
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MedLine Citation:
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PMID: 16601083 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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4-Chloro-m-cresol (4-CmC) is a clinically relevant activator of the intracellular Ca2+ release channel, the ryanodine receptor isoform 1 (RyR1). In this study, the chemical moieties on the 4-CmC molecule required for its activation of RyR1 were determined using structure-activity relationship analysis with a set of commercially available 4-CmC analogs. Separate compounds each lacking one of the three functional groups of 4-CmC (1-hydroxyl, 3-methyl, or 4-chloro) were poor activators of RyR1. Substitution of different chemical groups for the 1-hydroxyl of 4-CmC resulted in compounds that were poor activators of RyR1, suggesting that the hydroxyl group is preferred at this position. Substitution of hydrophobic groups at the 3-position enhanced bioactivity of the compound relative to 4-CmC, whereas substitution with hydrophilic groups abolished bioactivity. Likewise, 4-CmC analogs with hydrophobic groups substituted into the 4-position enhanced bioactivity, whereas hydrophilic or charged groups diminished bioactivity. 4-CmC analogs containing a single hydrophobic group at either the 3- or 4-position as well as 3,5-disubstituted or 3,4,5-trisubstituted phenols were also effective activators of RyR1. These results indicate that the 1-hydroxyl group of 4-CmC is required for activation of RyR1 and that hydrophobic groups at the 3,4- and 5-positions are preferred. These findings suggest that the 4-CmC binding site on RyR1 most likely consists of a hydrophilic region to interact with the 1-hydroxyl as well as a hydrophobic region(s) to interact with chemical groups at the 3- and/or 4-positions of 4-CmC. |
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Authors:
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Alan R Jacobson; Scott T Moe; P D Allen; James D Fessenden |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-04-06 |
Journal Detail:
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Title: Molecular pharmacology Volume: 70 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 2006 Jul |
Date Detail:
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Created Date: 2006-06-22 Completed Date: 2006-10-24 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 259-66 Citation Subset: IM |
Affiliation:
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Absolute Science Inc., Cambridge, Massachusetts, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Binding Sites Binding, Competitive / drug effects Cresols / chemistry*, metabolism, pharmacology Dose-Response Relationship, Drug Muscle Fibers, Skeletal / cytology, drug effects, metabolism Radioligand Assay Ryanodine / metabolism Ryanodine Receptor Calcium Release Channel / genetics, metabolism* Structure-Activity Relationship Tritium |
| Grant Support | |
ID/Acronym/Agency:
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K01-AR052120-01A1/AR/NIAMS NIH HHS; R01-AR43640/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cresols; 0/Ryanodine Receptor Calcium Release Channel; 10028-17-8/Tritium; 15662-33-6/Ryanodine; 59-50-7/chlorocresol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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