GBR DOPAMINE TRANSPORTER BINDING:PHARMACOPHORE MODELING

描述（由申请人提供）：可卡因成瘾在美国和世界各地都是一个问题。对可卡因滥用的初步研究揭示了它对人体的成瘾性作用。可卡因的成瘾性被认为与其与几种神经递质转运体，尤其是多巴胺转运体（DAT）的结合有关。

DESCRIPTION (provided by applicant): 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