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Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile

[Image: see text] Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT(1A) receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Co...

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Autores principales: Sniecikowska, Joanna, Gluch-Lutwin, Monika, Bucki, Adam, Więckowska, Anna, Siwek, Agata, Jastrzebska-Wiesek, Magdalena, Partyka, Anna, Wilczyńska, Daria, Pytka, Karolina, Latacz, Gniewomir, Przejczowska-Pomierny, Katarzyna, Wyska, Elżbieta, Wesołowska, Anna, Pawłowski, Maciej, Newman-Tancredi, Adrian, Kolaczkowski, Marcin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586344/
https://www.ncbi.nlm.nih.gov/pubmed/32883072
http://dx.doi.org/10.1021/acs.jmedchem.0c00814
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author Sniecikowska, Joanna
Gluch-Lutwin, Monika
Bucki, Adam
Więckowska, Anna
Siwek, Agata
Jastrzebska-Wiesek, Magdalena
Partyka, Anna
Wilczyńska, Daria
Pytka, Karolina
Latacz, Gniewomir
Przejczowska-Pomierny, Katarzyna
Wyska, Elżbieta
Wesołowska, Anna
Pawłowski, Maciej
Newman-Tancredi, Adrian
Kolaczkowski, Marcin
author_facet Sniecikowska, Joanna
Gluch-Lutwin, Monika
Bucki, Adam
Więckowska, Anna
Siwek, Agata
Jastrzebska-Wiesek, Magdalena
Partyka, Anna
Wilczyńska, Daria
Pytka, Karolina
Latacz, Gniewomir
Przejczowska-Pomierny, Katarzyna
Wyska, Elżbieta
Wesołowska, Anna
Pawłowski, Maciej
Newman-Tancredi, Adrian
Kolaczkowski, Marcin
author_sort Sniecikowska, Joanna
collection PubMed
description [Image: see text] Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT(1A) receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT(1A) receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
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spelling pubmed-75863442020-10-27 Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile Sniecikowska, Joanna Gluch-Lutwin, Monika Bucki, Adam Więckowska, Anna Siwek, Agata Jastrzebska-Wiesek, Magdalena Partyka, Anna Wilczyńska, Daria Pytka, Karolina Latacz, Gniewomir Przejczowska-Pomierny, Katarzyna Wyska, Elżbieta Wesołowska, Anna Pawłowski, Maciej Newman-Tancredi, Adrian Kolaczkowski, Marcin J Med Chem [Image: see text] Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT(1A) receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT(1A) receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects. American Chemical Society 2020-09-04 2020-10-08 /pmc/articles/PMC7586344/ /pubmed/32883072 http://dx.doi.org/10.1021/acs.jmedchem.0c00814 Text en This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Sniecikowska, Joanna
Gluch-Lutwin, Monika
Bucki, Adam
Więckowska, Anna
Siwek, Agata
Jastrzebska-Wiesek, Magdalena
Partyka, Anna
Wilczyńska, Daria
Pytka, Karolina
Latacz, Gniewomir
Przejczowska-Pomierny, Katarzyna
Wyska, Elżbieta
Wesołowska, Anna
Pawłowski, Maciej
Newman-Tancredi, Adrian
Kolaczkowski, Marcin
Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title_full Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title_fullStr Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title_full_unstemmed Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title_short Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT(1A) Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
title_sort discovery of novel perk1/2- or β-arrestin-preferring 5-ht(1a) receptor-biased agonists: diversified therapeutic-like versus side effect profile
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586344/
https://www.ncbi.nlm.nih.gov/pubmed/32883072
http://dx.doi.org/10.1021/acs.jmedchem.0c00814
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