Document Detail

Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter.
MedLine Citation:
PMID:  12213055     Owner:  NLM     Status:  MEDLINE    
A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of mazindol analogues using the comparative molecular field analysis (CoMFA) method with their corresponding binding affinities for the displacement of [(3)H]WIN 35 428 from rat caudate putamen tissue. The cross-validated CoMFA models were derived from a training set of 50 compounds, and the predictive ability of the resulting CoMFA models was evaluated against a test set of 21 compounds. A set of alignment rules was derived to superimpose these compounds onto a template structure, mazindol (1). These CoMFA models yielded significant cross-validated r(2)(cv) values. Inclusion of additional descriptors did not improve the significance of the CoMFA models; thus, steric and electrostatic fields are the relevant descriptors for these compounds. The best QSAR model was selected on the basis of the predictive ability of the activity on the external test set of compounds. The analysis of coefficient contour maps provided further insight into the binding interactions of mazindol analogues with the DAT. The aromatic rings C and D are involved in hydrophobic interactions in which ring D may bind in a large hydrophobic groove. The relative orientation of these two rings is also important for high binding affinity to the DAT.
Santosh S Kulkarni; Amy Hauck Newman; William J Houlihan
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  45     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-05     Completed Date:  2002-10-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4119-27     Citation Subset:  IM    
Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
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MeSH Terms
Binding Sites
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors / chemistry*,  metabolism
Mazindol / analogs & derivatives*,  chemistry*,  metabolism
Membrane Glycoproteins*
Membrane Transport Proteins / chemistry*,  metabolism
Models, Molecular
Nerve Tissue Proteins*
Putamen / metabolism
Quantitative Structure-Activity Relationship
Radioligand Assay
Grant Support
Reg. No./Substance:
0/Dopamine Plasma Membrane Transport Proteins; 0/Dopamine Uptake Inhibitors; 0/Membrane Glycoproteins; 0/Membrane Transport Proteins; 0/Nerve Tissue Proteins; 0/Slc6a3 protein, rat; 22232-71-9/Mazindol

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