Source:http://linkedlifedata.com/resource/pubmed/id/15860577
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
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| pubmed:dateCreated |
2005-7-18
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| pubmed:abstractText |
Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine analogs (4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1-099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K(i) = 439 nM), was inactive at NET binding ([(3)H]nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [(125)I]RTI-55 binding to hSERT with an extrapolated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K(d) and B(max) of [(125)I]RTI-55 binding to hSERT, we found that TB-1-099 decreased the B(max) in a dose-dependent manner and affected the apparent K(d) in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K(d) but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [(3)H]5-HT, but not [(3)H]dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [(125)I]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [(125)I]RTI-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function.
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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/Benzhydryl Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Cocaine,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neurotransmitter Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/RTI 55,
http://linkedlifedata.com/resource/pubmed/chemical/SLC6A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Plasma Membrane...,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Uptake Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Slc6a4 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/vanoxerine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
0022-3565
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
314
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
906-15
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:15860577-Animals,
pubmed-meshheading:15860577-Benzhydryl Compounds,
pubmed-meshheading:15860577-Binding, Competitive,
pubmed-meshheading:15860577-Brain,
pubmed-meshheading:15860577-Cell Line,
pubmed-meshheading:15860577-Cocaine,
pubmed-meshheading:15860577-Dopamine,
pubmed-meshheading:15860577-Humans,
pubmed-meshheading:15860577-Kinetics,
pubmed-meshheading:15860577-Male,
pubmed-meshheading:15860577-Membrane Glycoproteins,
pubmed-meshheading:15860577-Membrane Transport Proteins,
pubmed-meshheading:15860577-Nerve Tissue Proteins,
pubmed-meshheading:15860577-Neurotransmitter Agents,
pubmed-meshheading:15860577-Piperazines,
pubmed-meshheading:15860577-Piperidines,
pubmed-meshheading:15860577-Protein Binding,
pubmed-meshheading:15860577-Rats,
pubmed-meshheading:15860577-Rats, Sprague-Dawley,
pubmed-meshheading:15860577-Serotonin,
pubmed-meshheading:15860577-Serotonin Plasma Membrane Transport Proteins,
pubmed-meshheading:15860577-Serotonin Uptake Inhibitors
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| pubmed:year |
2005
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| pubmed:articleTitle |
Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter.
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| pubmed:affiliation |
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
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| pubmed:publicationType |
Journal Article,
In Vitro
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