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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
1998-3-6
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pubmed:abstractText |
(3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/(1R-(exo,exo))-3-(4-fluorophenyl)-8-...,
http://linkedlifedata.com/resource/pubmed/chemical/Cocaine,
http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Uptake Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Paroxetine,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Uptake Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Tropanes
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
247-57
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:9457247-Binding, Competitive,
pubmed-meshheading:9457247-Cocaine,
pubmed-meshheading:9457247-Dopamine Uptake Inhibitors,
pubmed-meshheading:9457247-Isomerism,
pubmed-meshheading:9457247-Ligands,
pubmed-meshheading:9457247-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9457247-Models, Chemical,
pubmed-meshheading:9457247-Models, Molecular,
pubmed-meshheading:9457247-Paroxetine,
pubmed-meshheading:9457247-Receptors, Serotonin,
pubmed-meshheading:9457247-Serotonin Uptake Inhibitors,
pubmed-meshheading:9457247-Structure-Activity Relationship,
pubmed-meshheading:9457247-Tropanes
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pubmed:year |
1998
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pubmed:articleTitle |
Synthesis and ligand binding of tropane ring analogues of paroxetine.
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pubmed:affiliation |
Research Triangle Institute, North Carolina 27709, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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