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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
22
|
| pubmed:dateCreated |
1995-12-26
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| pubmed:abstractText |
A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2,3,4,5-Tetrahydro-7,8-dihydroxy-1-p...,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic alpha-1 Receptor...,
http://linkedlifedata.com/resource/pubmed/chemical/Antipsychotic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Indans,
http://linkedlifedata.com/resource/pubmed/chemical/Oxidopamine,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D2,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Antagonists
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
27
|
| pubmed:volume |
38
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4380-92
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| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:7473566-2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine,
pubmed-meshheading:7473566-3T3 Cells,
pubmed-meshheading:7473566-Adrenergic Agents,
pubmed-meshheading:7473566-Adrenergic alpha-1 Receptor Antagonists,
pubmed-meshheading:7473566-Animals,
pubmed-meshheading:7473566-Antipsychotic Agents,
pubmed-meshheading:7473566-Dopamine Antagonists,
pubmed-meshheading:7473566-Indans,
pubmed-meshheading:7473566-Mice,
pubmed-meshheading:7473566-Oxidopamine,
pubmed-meshheading:7473566-Piperazines,
pubmed-meshheading:7473566-Rats,
pubmed-meshheading:7473566-Receptors, Adrenergic, alpha-1,
pubmed-meshheading:7473566-Receptors, Dopamine D1,
pubmed-meshheading:7473566-Receptors, Dopamine D2,
pubmed-meshheading:7473566-Serotonin Antagonists,
pubmed-meshheading:7473566-Structure-Activity Relationship
|
| pubmed:year |
1995
|
| pubmed:articleTitle |
Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.
|
| pubmed:affiliation |
Research & Development, H. Lundbeck A/S, Copenhagen, Valby, Denmark.
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| pubmed:publicationType |
Journal Article
|