Document Detail

Structural determinants of 4-chloro-m-cresol required for activation of ryanodine receptor type 1.
MedLine Citation:
PMID:  16601083     Owner:  NLM     Status:  MEDLINE    
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.
Alan R Jacobson; Scott T Moe; P D Allen; James D Fessenden
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-04-06
Journal Detail:
Title:  Molecular pharmacology     Volume:  70     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-22     Completed Date:  2006-10-24     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  259-66     Citation Subset:  IM    
Absolute Science Inc., Cambridge, Massachusetts, USA.
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MeSH Terms
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
Grant Support
Reg. No./Substance:
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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