Linked Life Data

12825932

Source:http://linkedlifedata.com/resource/pubmed/id/12825932

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2003-6-26
pubmed:abstractText
Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2beta-carboalkoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [(3)H]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K(i) = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2beta-carbophenylethoxy-3alpha-(bis[4-fluorophenyl]methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC(50) = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
3
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2908-16
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12825932-Animals, pubmed-meshheading:12825932-Binding, Competitive, pubmed-meshheading:12825932-Brain, pubmed-meshheading:12825932-Chlorine, pubmed-meshheading:12825932-Dopamine, pubmed-meshheading:12825932-Dopamine Plasma Membrane Transport Proteins, pubmed-meshheading:12825932-Fluorine, pubmed-meshheading:12825932-Ligands, pubmed-meshheading:12825932-Membrane Glycoproteins, pubmed-meshheading:12825932-Membrane Transport Proteins, pubmed-meshheading:12825932-Models, Molecular, pubmed-meshheading:12825932-Nerve Tissue Proteins, pubmed-meshheading:12825932-Radioligand Assay, pubmed-meshheading:12825932-Rats, pubmed-meshheading:12825932-Stereoisomerism, pubmed-meshheading:12825932-Structure-Activity Relationship, pubmed-meshheading:12825932-Synaptosomes, pubmed-meshheading:12825932-Tropanes
pubmed:year
2003
pubmed:articleTitle
Structure-activity relationship comparison of (S)-2beta-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes and (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes at the dopamine transporter.
pubmed:affiliation
Medicinal Chemistry and Psychobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S.