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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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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. |
format | Online Article Text |
id | pubmed-7586344 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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