Document Detail


Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.
MedLine Citation:
PMID:  12213054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of mazindol (1), homomazindol (2), and bishomomazindol (3) derivatives with a benzo or cyclohexano ring fused at various sites were prepared as part of an SAR study to determine the effect of increased aliphatic and aromatic lipophilicity on selected in vitro assays used to identify potential cocaine-like and cocaine antagonism activity. Very good (IC(50) = 2-3 nM) inhibition of [(3)H] WIN 35,428 and [(125)I] RTI-55 binding on rat or guinea pig striatal membranes and HEK cells expressing cDNA for the human dopamine transporter (HEK-hDAT) was shown by the 8,9-benzomazindol 25 and 9,10-benzohomomazindol 28. All new compounds were weaker inhibitors of [(3)H] DA uptake in HEK-hDAT cells than 1 and 2. No improvement in the binding selectivity ratio (SERT/DAT and NET/DAT) was found when compared to 2. Compounds 25and 28 showed a considerable increase versus 1 in uptake/binding discrimination ratios at the DAT (311.0 and 182.1 vs 0.9), SERT (33.6 and 127.3 vs 1.9), and NET (7.3 and 10.0 vs 0.3).
Authors:
William J Houlihan; Umer F Ahmad; Judith Koletar; Lawrence Kelly; Leonard Brand; Theresa A Kopajtic
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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:  4110-8     Citation Subset:  IM    
Affiliation:
Charles A. Dana Research Institute, Drew University, Hall of Sciences, Madison, NJ 07940, USA. whouliha@drew.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Cell Line
Central Nervous System Stimulants / metabolism*
Cocaine / metabolism*
Corpus Striatum / metabolism
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors / chemical synthesis*,  chemistry,  pharmacology
Guinea Pigs
Humans
Male
Mazindol / chemical synthesis*,  chemistry,  pharmacology
Membrane Glycoproteins*
Membrane Transport Modulators*
Membrane Transport Proteins / antagonists & inhibitors*,  metabolism
Nerve Tissue Proteins*
Radioligand Assay
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
N01 DA 38303/DA/NIDA NIH HHS; R01 DA 10533-01/DA/NIDA NIH HHS; R03 DA 08516-02/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Central Nervous System Stimulants; 0/Dopamine Plasma Membrane Transport Proteins; 0/Dopamine Uptake Inhibitors; 0/Membrane Glycoproteins; 0/Membrane Transport Modulators; 0/Membrane Transport Proteins; 0/Nerve Tissue Proteins; 0/SLC6A3 protein, human; 0/Slc6a3 protein, rat; 22232-71-9/Mazindol; 50-36-2/Cocaine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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