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Exploration of the accessory binding region in the D1 dopamine receptor.

机译：探索D1多巴胺受体中的辅助结合区。

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摘要

To gain a better understanding of the functional topography of the D 1 dopamine receptor accessory binding region, a series of ligands possessing a pendant phenyl substituent was synthesized and evaluated for their D 1-like and D2-like receptor affinities and functional activities. Conformational analysis of structurally-restricted analogs of SKF 38393 and ring-expanded analogs of doxthanrine demonstrated the importance of the orientation of the β-phenyl ring for receptor affinity and activity. The placement of the β-phenyl ring must be well defined with very little tolerance for conformational variability. In order to achieve high affinity and full agonist activity, the amine nitrogen should be positioned in the same plane as the catechol ring, with the β-phenyl substituent oriented slightly above and close to planarity with the catechol plane. To explore the accessory region beyond the β-phenyl ring binding site, compounds 9 and 10 with their pendant phenyl ring displaced two atoms from the β-position were synthesized. Molecular modeling of 9 and 10 not only identified potential residues in the accessory region that are crucial for ligand-receptor interactions, but also helped further define the boundary of this binding pocket. In addition, synthesis of 10 led to the development of a new class of potent, selective D2 agonist. SAR studies of 10 and its pendant ring-substituted analogs indicated the presence of an accessory ring binding site in the D 2 receptor, and provided preliminary data on the electronic properties of this region. Overall, these results have deepened our understanding of the D1 receptor binding site.
机译：为了更好地理解D 1多巴胺受体辅助结合区的功能拓扑，合成了一系列具有侧苯基取代基的配体，并评估了它们的D 1类和D2类受体亲和力和功能活性。对SKF 38393的结构受限的类似物和多克他林的环扩展类似物的构象分析表明，β-苯环的取向对于受体亲和力和活性很重要。必须很好地定义β-苯环的位置，并且对构象变异性的公差很小。为了获得高亲和力和充分的激动剂活性，胺氮应与邻苯二酚环位于同一平面，且β-苯基取代基的取向略高于邻苯二酚平面，且与邻苯二酚平面接近。为了探索β-苯环结合位点以外的辅助区域，合成了化合物9和10，它们的侧苯环侧移了两个β位。 9和10的分子模型不仅识别了对配体-受体相互作用至关重要的辅助区域中的潜在残基，而且还帮助进一步定义了该结合口袋的边界。此外，合成10导致开发了新型的有效，选择性D2激动剂。对10及其悬挂的环取代类似物的SAR研究表明，D 2受体中存在辅助环结合位点，并提供了有关该区域电子特性的初步数据。总体而言，这些结果加深了我们对D1受体结合位点的了解。

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  • 作者

    Clark, Alia Huang.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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