Linked Life Data

11425577

Source:http://linkedlifedata.com/resource/pubmed/id/11425577

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2001-6-26
pubmed:abstractText
We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that (+/-)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structure-activity relationship study led to identification of a more potent DAT inhibitor [(+/-)-4] but this compound failed to show any significant functional antagonism. To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with K(i) values of 0.041--0.30 and 0.052--0.16 microM in [(3)H]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (-)-isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (-)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (-)-3 showed that (-)-3 is responsible for the functional antagonism obtained with the original lead (+/-)-3. Out of the new compounds synthesized, analogue (+/-)-20, which is 8- and 3-fold more potent than (+/-)-3 in binding and inhibition of DA reuptake, appeared to have improved functional antagonism as compared to (+/-)-3.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0968-0896
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1753-64
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11425577-Animals, pubmed-meshheading:11425577-Carrier Proteins, pubmed-meshheading:11425577-Chromatography, High Pressure Liquid, pubmed-meshheading:11425577-Corpus Striatum, pubmed-meshheading:11425577-Dopamine, pubmed-meshheading:11425577-Dopamine Plasma Membrane Transport Proteins, pubmed-meshheading:11425577-Magnetic Resonance Spectroscopy, pubmed-meshheading:11425577-Membrane Glycoproteins, pubmed-meshheading:11425577-Membrane Transport Proteins, pubmed-meshheading:11425577-Models, Molecular, pubmed-meshheading:11425577-Nerve Tissue Proteins, pubmed-meshheading:11425577-Norepinephrine, pubmed-meshheading:11425577-Piperidines, pubmed-meshheading:11425577-Rats, pubmed-meshheading:11425577-Serotonin, pubmed-meshheading:11425577-Structure-Activity Relationship, pubmed-meshheading:11425577-Synaptosomes
pubmed:year
2001
pubmed:articleTitle
Molecular modeling, structure--activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors.
pubmed:affiliation
Department of Oncology, Georgetown University Medical Center, Building D, Room 235/237 4000 Reservoir Rd, Washington, DC 20007, USA. wangs@georgetown.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.