کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1394086 1501136 2014 28 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Towards the development of 5-HT7 ligands combining serotonin-like and arylpiperazine moieties
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Towards the development of 5-HT7 ligands combining serotonin-like and arylpiperazine moieties
چکیده انگلیسی


• Potent 5-HT7 ligands can combine a serotonin-like and an arylpiperazine moiety.
• The serotonin-like portion can be replaced by a hydroxyanilinoalkyl one.
• The two moieties can be docked into different binding pockets of 5-HT7 receptor.
• Among the newly synthesized compounds, potent ligands were identified.

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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 80, 10 June 2014, Pages 8–35
نویسندگان
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