Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Abstract 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-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imid...

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Autores principales:	Adam S. Hogendorf, Agata Hogendorf, Rafał Kurczab, Grzegorz Satała, Tomasz Lenda, Maria Walczak, Gniewomir Latacz, Jadwiga Handzlik, Katarzyna Kieć-Kononowicz, Joanna M. Wierońska, Monika Woźniak, Paulina Cieślik, Ryszard Bugno, Jakub Staroń, Andrzej J. Bojarski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b2815ce3d4e34da783160c0d85d688cb
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spelling	oai:doaj.org-article:b2815ce3d4e34da783160c0d85d688cb2021-12-02T12:31:53ZLow-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol10.1038/s41598-017-00822-42045-2322https://doaj.org/article/b2815ce3d4e34da783160c0d85d688cb2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00822-4https://doaj.org/toc/2045-2322Abstract 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-HT7 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, EC50 = 19 nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC50 = 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 (Cmax = 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-HT7R 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-HT1AR selectivity.Adam S. HogendorfAgata HogendorfRafał KurczabGrzegorz SatałaTomasz LendaMaria WalczakGniewomir LataczJadwiga HandzlikKatarzyna Kieć-KononowiczJoanna M. WierońskaMonika WoźniakPaulina CieślikRyszard BugnoJakub StarońAndrzej J. BojarskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Adam S. Hogendorf Agata Hogendorf Rafał Kurczab Grzegorz Satała Tomasz Lenda Maria Walczak Gniewomir Latacz Jadwiga Handzlik Katarzyna Kieć-Kononowicz Joanna M. Wierońska Monika Woźniak Paulina Cieślik Ryszard Bugno Jakub Staroń Andrzej J. Bojarski Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
description	Abstract 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-HT7 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, EC50 = 19 nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC50 = 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 (Cmax = 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-HT7R 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-HT1AR selectivity.
format	article
author	Adam S. Hogendorf Agata Hogendorf Rafał Kurczab Grzegorz Satała Tomasz Lenda Maria Walczak Gniewomir Latacz Jadwiga Handzlik Katarzyna Kieć-Kononowicz Joanna M. Wierońska Monika Woźniak Paulina Cieślik Ryszard Bugno Jakub Staroń Andrzej J. Bojarski
author_facet	Adam S. Hogendorf Agata Hogendorf Rafał Kurczab Grzegorz Satała Tomasz Lenda Maria Walczak Gniewomir Latacz Jadwiga Handzlik Katarzyna Kieć-Kononowicz Joanna M. Wierońska Monika Woźniak Paulina Cieślik Ryszard Bugno Jakub Staroń Andrzej J. Bojarski
author_sort	Adam S. Hogendorf
title	Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_short	Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_full	Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_fullStr	Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_full_unstemmed	Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
title_sort	low-basicity 5-ht7 receptor agonists synthesized using the van leusen multicomponent protocol
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b2815ce3d4e34da783160c0d85d688cb
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Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

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