GBR DOPAMINE TRANSPORTER BINDING:PHARMACOPHORE MODELING

描述(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上瘾作用。可卡因的成瘾作用被认为与其与几种神经转运体，特别是多巴胺转运体(DAT)的结合有关。 可卡因是一种多巴胺再摄取抑制剂，可导致DAT摄取较少的多巴胺。GBR系列二烷基哌嗪已被确定为选择性多巴胺摄取抑制剂，可用于治疗可卡因成瘾。这些化合物已经在实验室中使用传统的构效关系技术进行了探索，但还没有使用分子建模方法进行药效团开发。 这项研究的目的是确定两个药效团：一个是DAT结合位点，另一个是DAT的多巴胺摄取。药效团将使用在真空中进行的比较分子场分析(CoMFA)研究来开发，并通过在溶剂中重复研究来改进结果。将使用偏最小二乘法对CoMFA结果与结合和再摄取数据进行建模。将根据最具预测性的模型选择生物活性构象，然后将其用作药效团的基础

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