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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2002-1-10
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pubmed:abstractText |
The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3,4-Dihydroxyphenylacetic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/7-chloro-9-(4-methylpiperazin-1-yl)-...,
http://linkedlifedata.com/resource/pubmed/chemical/Antipsychotic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Homovanillic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Prolactin,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D2,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazepines
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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-author:ButiniStefaniaS,
pubmed-author:CagnottoAlfredoA,
pubmed-author:CampianiGiuseppeG,
pubmed-author:CarminatiPaoloP,
pubmed-author:CastorinaMassimoM,
pubmed-author:CatalanottiBrunoB,
pubmed-author:Di CesareM AssuntaMA,
pubmed-author:FattorussoCaterinaC,
pubmed-author:GallettiBrunoB,
pubmed-author:GemmaSandraS,
pubmed-author:GhirardiOrlandoO,
pubmed-author:GiorgiGianlucaG,
pubmed-author:GoeganMaraM,
pubmed-author:MastroianniDomenicoD,
pubmed-author:MenniniTizianaT,
pubmed-author:MinettiPatriziaP,
pubmed-author:NacciVitoV,
pubmed-author:PacificiLiciaL,
pubmed-author:ScafettaNazzarenoN,
pubmed-author:StasiM AntoniettaMA,
pubmed-author:TintiOrnellaO
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pubmed:issnType |
Print
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pubmed:day |
17
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pubmed:volume |
45
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
344-59
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11784139-3,4-Dihydroxyphenylacetic Acid,
pubmed-meshheading:11784139-Animals,
pubmed-meshheading:11784139-Antipsychotic Agents,
pubmed-meshheading:11784139-Behavior, Animal,
pubmed-meshheading:11784139-Brain,
pubmed-meshheading:11784139-Catalepsy,
pubmed-meshheading:11784139-Crystallography, X-Ray,
pubmed-meshheading:11784139-Dopamine,
pubmed-meshheading:11784139-Dopamine Antagonists,
pubmed-meshheading:11784139-Homovanillic Acid,
pubmed-meshheading:11784139-Male,
pubmed-meshheading:11784139-Mice,
pubmed-meshheading:11784139-Microdialysis,
pubmed-meshheading:11784139-Models, Molecular,
pubmed-meshheading:11784139-Molecular Conformation,
pubmed-meshheading:11784139-Molecular Structure,
pubmed-meshheading:11784139-Prolactin,
pubmed-meshheading:11784139-Pyrroles,
pubmed-meshheading:11784139-Radioligand Assay,
pubmed-meshheading:11784139-Rats,
pubmed-meshheading:11784139-Rats, Inbred F344,
pubmed-meshheading:11784139-Rats, Wistar,
pubmed-meshheading:11784139-Receptors, Dopamine D2,
pubmed-meshheading:11784139-Stereoisomerism,
pubmed-meshheading:11784139-Structure-Activity Relationship,
pubmed-meshheading:11784139-Thiazepines
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pubmed:year |
2002
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pubmed:articleTitle |
Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies.
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pubmed:affiliation |
Dipartimento Farmaco Chimico Tecnologico, Universitá degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy. campiani@unisi.it
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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