Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino, PU, Italy.
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy.
Eur J Med Chem. 2014 Jun 10;80:8-35. doi: 10.1016/j.ejmech.2014.04.034. Epub 2014 Apr 13.
Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin-like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule.
许多已知的 5-HT7 配体含有类似血清素的结构或芳基哌嗪结构，在已发表的 SAR 研究中，通常认为这两种结构结合相同的受体口袋。相反，我们探索了这样一种假设，即两个这样的部分可以共存于同一个配体中，结合到不同的口袋中。因此，我们设计并合成了一组包括 5-羟吲哚-3-乙氧基和 1-芳基哌嗪部分的化合物，它们通过短连接子连接。这些化合物被测试了对人 5-HT7 血清素受体的亲和力。我们进一步制备了一系列新型 5-HT7 配体，其中 5-羟吲哚-3-乙氧基部分被生物等排体 3-羟基苯胺基烷基取代。在所合成的新化合物中，鉴定出了对 5-HT7 受体具有高亲和力的配体，在功能测试中表现为拮抗剂，尽管它们显示出有限的亚型选择性。在 5-HT7 受体模型中的对接研究表明，该结合位点实际上可以容纳两个部分，类似血清素的部分位于假定的正位点，芳基哌嗪部分占据辅助口袋。本研究结果表明，有可能设计和开发新的 5-HT7 配体，将两种优势结构合并到同一个分子中。
