...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Medicinal Chemistry >Highly selective chiral N-substituted 3alpha-(bis(4'-fluorophenyl)methoxy)tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis.
【24h】

Highly selective chiral N-substituted 3alpha-(bis(4'-fluorophenyl)methoxy)tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis.

机译：多巴胺转运蛋白的高选择性手性N-取代3α-（双（4'-氟苯基）甲氧基）托烷类似物：合成和比较分子场分析。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

In a continuing effort to further characterize the role of the dopamine transporter in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3alpha-[bis(4'-fluorophenyl)methoxy]tropane (5) has been prepared as potential selective dopamine transporter ligands. These novel compounds displaced [(3)H]WIN 35,428 binding from the dopamine transporter in rat caudate putamen with K(i) values ranging from 13. 9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly higher affinity for the dopamine transporter than the parent drug, 3alpha-(diphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective over muscarinic m(1) receptors (dopamine transporter, K(i) = 11.8 nM; m(1), K(i) = 11.6 nM) which could potentially confound the interpretation of behavioral data, for this compound and other members of this series. Thus, significant effort has been directed toward developing analogues that retain high affinity at the dopamine transporter but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affinity at the dopamine transporter (K(i) = 8.51 nM) while decreasing affinity at muscarinic receptors (K(i) = 576 nM) was achieved, resulting in 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S)-N-(2-amino-3-methyl-n-butyl)-3alpha-[bis(4'-fluorophenyl)metho xy] tropane (10b) showing a 136-fold selectivity for the dopamine transporter versus muscarinic m(1) receptors (K(i) = 29.5 nM versus K(i) = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q(2) = 0. 746) was used to accurately predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a visual representation of the chemical environment of the binding domain of the dopamine transporter, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors.
机译：为了进一步表征多巴胺转运蛋白在可卡因药理作用中的作用，已制备了一系列3α-[双（4'-氟苯基）甲氧基]托烷的手性和非手性N-取代类似物（5）作为潜在的选择性多巴胺转运蛋白配体。这些新化合物取代了大鼠尾状壳中多巴胺转运蛋白的[（3）H] WIN 35,428结合，其K（i）值为13. 9至477 nM。以前，有报道称5对母体药物多巴胺转运蛋白的亲和力明显高于母体药物3alpha-（diphenylmethoxy）tropane（3;苯甲平）。但是，仍有5个对毒蕈碱m（1）受体（多巴胺转运蛋白，K（i）= 11.8 nM; m（1），K（i）= 11.6 nM）具有非选择性，这可能会混淆该化合物的行为数据解释。和该系列的其他成员。因此，已致力于开发在多巴胺转运蛋白上保持高亲和力但在毒蕈碱位点具有降低的亲和力的类似物。最近，发现通过用苯基-正丁基取代基（6）取代5的N-甲基，保留了对多巴胺转运蛋白的高结合亲和力（K（i）= 8.51 nM），同时降低了对毒蕈碱受体的亲和力。 （K（i）= 576 nM）达到了68倍的选择性。在本系列中，通过手性类似物（S）-N-（2-氨基-3-甲基-正丁基）-3alpha- [双（4'-对多巴胺转运蛋白相对于毒蕈碱m（1）受体具有136倍的选择性（分别为K（i）= 29.5 nM和K（i）= 4020 nM）。此外，推导了比较分子场分析（CoMFA）模型，以关联我们已经制备的所有N-取代的3α-[双（4'-氟苯基）甲氧基]托烷类似物的结合亲和力及其3D结构特征。最佳模型（q（2）= 0. 746）用于准确预测训练集中和测试集中化合物的结合亲和力。该模型的CoMFA系数等值线图可直观表示多巴胺转运蛋白结合域的化学环境，现在可用于设计和/或预测此类多巴胺摄取抑制剂中新药的结合亲和力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号