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Volume 14
Issue 10
10.3390/ph14100987
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Article

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

by
Egils Bisenieks
1,
Brigita Vigante
1,
Ramona Petrovska
2,
Baiba Turovska
1,
Ruslan Muhamadejev
1,
Vitalijs Soloduns
1,
Astrida Velena
1,
Karlis Pajuste
1,
Luciano Saso
3,
Janis Klovins
2,
Gunars Duburs
1,* and
Ilona Mandrika
2,*
1
Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia
2
Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia
3
Department of Physiology and Pharmacology “Vittorio Erspamer”, University Sapienza, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(10), 987; https://doi.org/10.3390/ph14100987
Submission received: 31 July 2021 / Revised: 9 September 2021 / Accepted: 22 September 2021 / Published: 28 September 2021
(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)
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Abstract

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.
Keywords: G-protein-coupled receptors; multi-target ligands; FFA3/GPR41; FFA2/GPR43; HCA2/GPR109A; electron-donating compounds G-protein-coupled receptors; multi-target ligands; FFA3/GPR41; FFA2/GPR43; HCA2/GPR109A; electron-donating compounds
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MDPI and ACS Style

Bisenieks, E.; Vigante, B.; Petrovska, R.; Turovska, B.; Muhamadejev, R.; Soloduns, V.; Velena, A.; Pajuste, K.; Saso, L.; Klovins, J.; et al. 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. Pharmaceuticals 2021, 14, 987. https://doi.org/10.3390/ph14100987

AMA Style

Bisenieks E, Vigante B, Petrovska R, Turovska B, Muhamadejev R, Soloduns V, Velena A, Pajuste K, Saso L, Klovins J, et al. 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. Pharmaceuticals. 2021; 14(10):987. https://doi.org/10.3390/ph14100987

Chicago/Turabian Style

Bisenieks, Egils, Brigita Vigante, Ramona Petrovska, Baiba Turovska, Ruslan Muhamadejev, Vitalijs Soloduns, Astrida Velena, Karlis Pajuste, Luciano Saso, Janis Klovins, and et al. 2021. "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" Pharmaceuticals 14, no. 10: 987. https://doi.org/10.3390/ph14100987

APA Style

Bisenieks, E., Vigante, B., Petrovska, R., Turovska, B., Muhamadejev, R., Soloduns, V., Velena, A., Pajuste, K., Saso, L., Klovins, J., Duburs, G., & Mandrika, I. (2021). 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. Pharmaceuticals, 14(10), 987. https://doi.org/10.3390/ph14100987

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