Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2009-12-16
pubmed:abstractText
MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1521-009X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
108-14
pubmed:meshHeading
pubmed-meshheading:19797605-Animals, pubmed-meshheading:19797605-Bile, pubmed-meshheading:19797605-Biocatalysis, pubmed-meshheading:19797605-Biotransformation, pubmed-meshheading:19797605-Chromatography, Liquid, pubmed-meshheading:19797605-Cytosol, pubmed-meshheading:19797605-Dogs, pubmed-meshheading:19797605-Glutathione, pubmed-meshheading:19797605-Glutathione Transferase, pubmed-meshheading:19797605-Haplorhini, pubmed-meshheading:19797605-Humans, pubmed-meshheading:19797605-Liver, pubmed-meshheading:19797605-Magnetic Resonance Spectroscopy, pubmed-meshheading:19797605-Male, pubmed-meshheading:19797605-Microsomes, Liver, pubmed-meshheading:19797605-Molecular Structure, pubmed-meshheading:19797605-NADP, pubmed-meshheading:19797605-Pyridines, pubmed-meshheading:19797605-Rats, pubmed-meshheading:19797605-Rats, Sprague-Dawley, pubmed-meshheading:19797605-Receptor, Cannabinoid, CB1, pubmed-meshheading:19797605-Species Specificity, pubmed-meshheading:19797605-Sulfur Compounds, pubmed-meshheading:19797605-Tandem Mass Spectrometry
pubmed:year
2010
pubmed:articleTitle
Glutathione S-transferase catalyzed desulfonylation of a sulfonylfuropyridine.
pubmed:affiliation
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey, USA.
pubmed:publicationType
Journal Article