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Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT(7) receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-...

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Autores principales: Hogendorf, Adam S., Hogendorf, Agata, Kurczab, Rafał, Satała, Grzegorz, Lenda, Tomasz, Walczak, Maria, Latacz, Gniewomir, Handzlik, Jadwiga, Kieć-Kononowicz, Katarzyna, Wierońska, Joanna M., Woźniak, Monika, Cieślik, Paulina, Bugno, Ryszard, Staroń, Jakub, Bojarski, Andrzej J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431432/
https://www.ncbi.nlm.nih.gov/pubmed/28473721
http://dx.doi.org/10.1038/s41598-017-00822-4
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author Hogendorf, Adam S.
Hogendorf, Agata
Kurczab, Rafał
Satała, Grzegorz
Lenda, Tomasz
Walczak, Maria
Latacz, Gniewomir
Handzlik, Jadwiga
Kieć-Kononowicz, Katarzyna
Wierońska, Joanna M.
Woźniak, Monika
Cieślik, Paulina
Bugno, Ryszard
Staroń, Jakub
Bojarski, Andrzej J.
author_facet Hogendorf, Adam S.
Hogendorf, Agata
Kurczab, Rafał
Satała, Grzegorz
Lenda, Tomasz
Walczak, Maria
Latacz, Gniewomir
Handzlik, Jadwiga
Kieć-Kononowicz, Katarzyna
Wierońska, Joanna M.
Woźniak, Monika
Cieślik, Paulina
Bugno, Ryszard
Staroń, Jakub
Bojarski, Andrzej J.
author_sort Hogendorf, Adam S.
collection PubMed
description A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT(7) receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K (i 5-HT7) = 6 nM, EC(50) = 19 nM, 176-fold selectivity over 5-HT(1A)R) and 1e (5-methoxy analogue, K (i 5-HT7) = 30 nM, EC(50) = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C(max) = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT(7)R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT(1A)R selectivity.
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spelling pubmed-54314322017-05-16 Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol Hogendorf, Adam S. Hogendorf, Agata Kurczab, Rafał Satała, Grzegorz Lenda, Tomasz Walczak, Maria Latacz, Gniewomir Handzlik, Jadwiga Kieć-Kononowicz, Katarzyna Wierońska, Joanna M. Woźniak, Monika Cieślik, Paulina Bugno, Ryszard Staroń, Jakub Bojarski, Andrzej J. Sci Rep Article A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT(7) receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K (i 5-HT7) = 6 nM, EC(50) = 19 nM, 176-fold selectivity over 5-HT(1A)R) and 1e (5-methoxy analogue, K (i 5-HT7) = 30 nM, EC(50) = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C(max) = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT(7)R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT(1A)R selectivity. Nature Publishing Group UK 2017-05-04 /pmc/articles/PMC5431432/ /pubmed/28473721 http://dx.doi.org/10.1038/s41598-017-00822-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hogendorf, Adam S.
Hogendorf, Agata
Kurczab, Rafał
Satała, Grzegorz
Lenda, Tomasz
Walczak, Maria
Latacz, Gniewomir
Handzlik, Jadwiga
Kieć-Kononowicz, Katarzyna
Wierońska, Joanna M.
Woźniak, Monika
Cieślik, Paulina
Bugno, Ryszard
Staroń, Jakub
Bojarski, Andrzej J.
Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_full Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_fullStr Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_full_unstemmed Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_short Low-basicity 5-HT(7) Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_sort low-basicity 5-ht(7) receptor agonists synthesized using the van leusen multicomponent protocol
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431432/
https://www.ncbi.nlm.nih.gov/pubmed/28473721
http://dx.doi.org/10.1038/s41598-017-00822-4
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