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首页> 外文学位 >Design, synthesis, and pharmacological evaluation of three series of lobelane analogs as inhibitors of the vesicular monoamine transporter (VMAT2).
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Design, synthesis, and pharmacological evaluation of three series of lobelane analogs as inhibitors of the vesicular monoamine transporter (VMAT2).

机译：设计，合成和药理学评估三个系列的环氧丙烷类似物作为水泡单胺转运蛋白（VMAT2）的抑制剂。

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摘要

Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane is a defunctionalized analog of Lobeline, a natural product found in Lobelia inflata which has been shown to bind to VMAT2 and inhibit its function. Rational drug design methodology and organic synthesis was used to generate a library of three series of lobelane analogs. In total, 107 compounds were synthesized and examined. Compounds were assayed for affinity in a high-throughput [3H] dihydrotetrabenazine (DTBZ) radioligand binding screen as well as for function in a [3H] DA uptake assay. Several compounds were identified which possess affinity as well as selectivity for the DTBZ binding site on VMAT2 [JPC-077 (Ki=0.19 microM), JPC-094 (Ki=0.15 microM), JPC-096 (Ki=0.19 microM), and JPC-106 (Ki=0.19 microM)]. The same four compounds exhibited inhibition of [3H]DA uptake [JPC-077 (Ki=9.3 nM), JPC-094 (Ki=13 nM), JPC-096 (Ki=20 nM), and JPC-106 (Ki=83 nM)]. With the assay data generated from the library of compounds, several structure activity relationship (SAR) based ligand based pharmacophore models were developed to guide future ligand design.
机译：甲基苯丙胺（METH）的滥用在美国和全世界都是一个严重的问题。 METH用户获得的奖励是由于METH与DA转运蛋白（DAT）以及囊泡单胺转运蛋白2（VMAT2）之间相互作用引起的细胞外多巴胺（DA）浓度增加。 METH使用者所获得的奖励导致了该药的进一步使用和随后的滥用。当前的项目研究了三个新颖的环氧乙烷类似物系列与囊泡单胺转运蛋白2（VMAT2）上的结合位点相互作用的能力，以试图抑制甲硫氨酸的作用。 Lobelane是Lobeline的去官能化类似物，Lobeline是在Lobelia inflata中发现的天然产物，已显示与VMAT2结合并抑制其功能。合理的药物设计方法和有机合成被用于生成三个系列的环氧丙烷类似物的文库。总共合成并检查了107种化合物。在高通量[3H]二氢丁苯那嗪（DTBZ）放射性配体结合筛选中测定化合物的亲和力，并在[3H] DA吸收测定法中测试其功能。鉴定了对VMAT2上的DTBZ结合位点具有亲和力和选择性的几种化合物[JPC-077（Ki = 0.19 microM），JPC-094（Ki = 0.15 microM），JPC-096（Ki = 0.19 microM）和JPC-106（Ki = 0.19 microM）]。相同的四种化合物显示出对[3H] DA吸收的抑制作用[JPC-077（Ki = 9.3 nM），JPC-094（Ki = 13 nM），JPC-096（Ki = 20 nM）和JPC-106（Ki = 83 nM）]。利用化合物库中产生的测定数据，开发了几种基于结构活性关系（SAR）的基于配体的药效团模型，以指导未来的配体设计。

著录项

  • 作者

    Culver, John P.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 330 p.
  • 总页数 330
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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