Cocaine addiction is a problem in the U.S. and around the world. Initial research into the abuse of cocaine revealed its addictive effects on the human body. Cocaine's addictive effects are thought to be related to its binding to several neurotransrnitter transporters, especially the dopamine transporter (DAT) ? ? Cocaine is a doparnine reuptake inhibitor which causes less dopamine to be taken up by the DAT. The GBR series of dialkyl piperazines have been identified as selective dopamine uptake inhibitors that could be used to treat cocaine addiction. These compounds have been explored in the laboratory using traditional structure-activity relationship techniques, but pharmacophore development using molecular modeling methods have not been performed on them.The proposed research is a comprehensive molecular modeling study of 300 GBR analogs. ? ? The purpose of the study is to identify two pharmacophores: one for the DAT binding site and one for dopamine uptake at the DAT. The pharmacophores will be developed using a Comparative Molecular Field Analysis (CoMFA) study performed in vacuum, and the results refined by repeating the study in solvent. The Partial Least Squares method will be used to model the CoMFA results versus the binding and reuptake data. A bioactive conformer will be selected based on the most predictive model, then used as the basis for the pharmacophores

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA015555-02
Application #
6665096
Study Section
Special Emphasis Panel (ZRG1-F05 (29))
Program Officer
Kline, Richard
Project Start
2002-09-24
Project End
2005-09-23
Budget Start
2003-09-24
Budget End
2004-09-23
Support Year
2
Fiscal Year
2003
Total Cost
$30,919
Indirect Cost
Name
Rutgers University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
075162990
City
Newark
State
NJ
Country
United States
Zip Code
07102
Pandit, Deepangi; Roosma, William; Misra, Milind et al. (2011) Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent. J Mol Model 17:181-200
Gilbert, Kathleen M; Boos, Terrence L; Dersch, Christina M et al. (2007) DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods. Bioorg Med Chem 15:1146-59
Gilbert, Kathleen M; Venanzi, Carol A (2006) Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs. J Comput Aided Mol Des 20:209-25
Fiorentino, Anna; Pandit, Deepangi; Gilbert, Kathleen M et al. (2006) Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909. J Comput Chem 27:609-20
Gilbert, Kathleen M; Skawinski, William J; Misra, Milind et al. (2004) Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods. J Comput Aided Mol Des 18:719-38