Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR1A agonists and 5-HTR2A antagonists for potential use in depression and anxiety disorders
Copyright © 2020 Elsevier Ltd. All rights reserved..
Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR1A (EC50 6.7 nM) and antagonist activity against 5-HTR2A (IC50 62.3 nM) and was selective over 5-HTR2C receptor (IC50 > 3333 nM) in the PathHunter® β-arrestin assays.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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Enthalten in: |
Bioorganic & medicinal chemistry letters - 30(2020), 16 vom: 15. Aug., Seite 127358 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Evans, Colleen A [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 01.06.2021 Date Revised 01.06.2021 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.bmcl.2020.127358 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM312092237 |
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520 | |a Copyright © 2020 Elsevier Ltd. All rights reserved. | ||
520 | |a Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR1A (EC50 6.7 nM) and antagonist activity against 5-HTR2A (IC50 62.3 nM) and was selective over 5-HTR2C receptor (IC50 > 3333 nM) in the PathHunter® β-arrestin assays | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a 5-HTR(1A) partial agonist | |
650 | 4 | |a 5-HTR(2A) antagonist | |
650 | 4 | |a Adatanserin | |
650 | 4 | |a Tandem alkylation | |
650 | 4 | |a Thioadatanserin | |
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700 | 1 | |a Baradaran-Noviri, Sarah |e verfasserin |4 aut | |
700 | 1 | |a Perez-Cervantes, Natalia |e verfasserin |4 aut | |
700 | 1 | |a Siegler, Maxime A |e verfasserin |4 aut | |
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