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The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have b...

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Autores principales: Bisenieks, Egils, Vigante, Brigita, Petrovska, Ramona, Turovska, Baiba, Muhamadejev, Ruslan, Soloduns, Vitalijs, Velena, Astrida, Pajuste, Karlis, Saso, Luciano, Klovins, Janis, Duburs, Gunars, Mandrika, Ilona
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537386/
https://www.ncbi.nlm.nih.gov/pubmed/34681211
http://dx.doi.org/10.3390/ph14100987
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author Bisenieks, Egils
Vigante, Brigita
Petrovska, Ramona
Turovska, Baiba
Muhamadejev, Ruslan
Soloduns, Vitalijs
Velena, Astrida
Pajuste, Karlis
Saso, Luciano
Klovins, Janis
Duburs, Gunars
Mandrika, Ilona
author_facet Bisenieks, Egils
Vigante, Brigita
Petrovska, Ramona
Turovska, Baiba
Muhamadejev, Ruslan
Soloduns, Vitalijs
Velena, Astrida
Pajuste, Karlis
Saso, Luciano
Klovins, Janis
Duburs, Gunars
Mandrika, Ilona
author_sort Bisenieks, Egils
collection PubMed
description The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have been synthesized in order to characterise their pleiotropic, multitarget activity on the FFA3/GPR41, FFA2/GPR43, and HCA2/GPR109A receptors. Hexahydroquinoline derivatives have been known to exhibit characteristic activity as FFA3/GPR41 ligands, but during this study we observed their impact on FFA2/GPR43 and HCA2/GPR109A receptors as well as their electron-donating activity. Oxopyranopyrimidine and thioxopyranopyrimidine type compounds have been studied as ligands of the HCA2/GPR109A receptor; nevertheless, they exhibited equal or higher activity towards FFA3/GPR41 and FFA2/GPR43 receptors. S-Alkyl derivatives of pyranopyrimidines that have not yet been studied as ligands of GPCRs were more active towards HCA2/GPR109A and FFA3/GPR41 receptors than towards FFA2/GPR43. Representative compounds from each synthesized series were able to decrease the lipopolysaccharide-induced gene expression and secretion of proinflammatory cytokines (IL-6, TNF-α) and of a chemokine (MCP-1) in THP-1 macrophages, resembling the effect of HCA2/GPR109A ligand niacin and the endogenous ligand propionate. This study revealed groups of compounds possessing multitarget activity towards several receptors. The obtained data could be useful for further development of multitarget ligands.
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spelling pubmed-85373862021-10-24 The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A Bisenieks, Egils Vigante, Brigita Petrovska, Ramona Turovska, Baiba Muhamadejev, Ruslan Soloduns, Vitalijs Velena, Astrida Pajuste, Karlis Saso, Luciano Klovins, Janis Duburs, Gunars Mandrika, Ilona Pharmaceuticals (Basel) Article The paradigm of ligand-receptor interactions postulated as “one compound—one target” has been evolving; a multi-target, pleiotropic approach is now considered to be realistic. Novel series of 1,4,5,6,7,8-hexahydro-5-oxoquinolines, pyranopyrimidines and S-alkyl derivatives of pyranopyrimidines have been synthesized in order to characterise their pleiotropic, multitarget activity on the FFA3/GPR41, FFA2/GPR43, and HCA2/GPR109A receptors. Hexahydroquinoline derivatives have been known to exhibit characteristic activity as FFA3/GPR41 ligands, but during this study we observed their impact on FFA2/GPR43 and HCA2/GPR109A receptors as well as their electron-donating activity. Oxopyranopyrimidine and thioxopyranopyrimidine type compounds have been studied as ligands of the HCA2/GPR109A receptor; nevertheless, they exhibited equal or higher activity towards FFA3/GPR41 and FFA2/GPR43 receptors. S-Alkyl derivatives of pyranopyrimidines that have not yet been studied as ligands of GPCRs were more active towards HCA2/GPR109A and FFA3/GPR41 receptors than towards FFA2/GPR43. Representative compounds from each synthesized series were able to decrease the lipopolysaccharide-induced gene expression and secretion of proinflammatory cytokines (IL-6, TNF-α) and of a chemokine (MCP-1) in THP-1 macrophages, resembling the effect of HCA2/GPR109A ligand niacin and the endogenous ligand propionate. This study revealed groups of compounds possessing multitarget activity towards several receptors. The obtained data could be useful for further development of multitarget ligands. MDPI 2021-09-28 /pmc/articles/PMC8537386/ /pubmed/34681211 http://dx.doi.org/10.3390/ph14100987 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bisenieks, Egils
Vigante, Brigita
Petrovska, Ramona
Turovska, Baiba
Muhamadejev, Ruslan
Soloduns, Vitalijs
Velena, Astrida
Pajuste, Karlis
Saso, Luciano
Klovins, Janis
Duburs, Gunars
Mandrika, Ilona
The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title_full The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title_fullStr The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title_full_unstemmed The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title_short The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A
title_sort specificity and broad multitarget properties of ligands for the free fatty acid receptors ffa3/gpr41 and ffa2/gpr43 and the related hydroxycarboxylic acid receptor hca2/gpr109a
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537386/
https://www.ncbi.nlm.nih.gov/pubmed/34681211
http://dx.doi.org/10.3390/ph14100987
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