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

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.

Effect of Cichorium glandulosum on intestinal microbiota and bile acid metabolism in db/db mice

“…As key bacterial metabolites produced by the intestinal microbiota in the colon, short-chain fatty acids play an important role in the metabolism of substances, maintenance of barrier function, regulation of angiogenesis, maintenance of immune homeostasis, and prevention of pathological environments. They maintain the acidic environment of the intestine, inhibit the growth of harmful bacteria (Akhtar et al, 2021;O'Riordan et al, 2022;Xu et al, 2022), and bind to G-protein-coupled receptor 43 to stimulate L cells to regulate energy utilization (Bisenieks et al, 2021).…”

“…As key bacterial metabolites produced by the intestinal microbiota in the colon, short‐chain fatty acids play an important role in the metabolism of substances, maintenance of barrier function, regulation of angiogenesis, maintenance of immune homeostasis, and prevention of pathological environments. They maintain the acidic environment of the intestine, inhibit the growth of harmful bacteria (Akhtar et al., 2021; O'Riordan et al., 2022; Xu et al., 2022), and bind to G‐protein‐coupled receptor 43 to stimulate L cells to regulate energy utilization (Bisenieks et al., 2021). To further investigate the effect of CG on the intestinal microbiota of db/db mice and the metabolites of short‐chain fatty acids, we sequenced the fecal intestinal bacteria of db/db mice by using a 16SrRNA amplicon sequencing technology and detected the content of short‐chain fatty acids in the feces of the db/db mice through gas chromatography.…”

Insights into the recent progress in the medicinal chemistry of pyranopyrimidine analogs

“…93 The antidiabetic activity of pyranopyrimidine-diones "series 128a-m" (Scheme 30) was estimated by Mehrabi et al 13 Also, compounds (series 129a′-m′) (Scheme 30) were assessed as antioxidant and glycohydrolase inhibitors as evaluated by Khodarahmi's group. 94 The results identified that compounds 129h′ Bisenieks et al 95 prepared a series of pyranopyrimidinediones 130a-g and their S-alkyl derivatives 131a-g from barbituric and thiobarbituric acids in multi-step synthetic routes (Scheme 31). The action of these compounds on the short-chain fatty acid receptors FFA2/GPR43 and FFA3/GPR41 was studied, in addition to evaluating their activity against hydroxy-carboxylic acid receptor HCA2/GPR109A.…”

“…Bisenieks et al 95 prepared a series of pyranopyrimidine-diones 130a–g and their S -alkyl derivatives 131a–g from barbituric and thiobarbituric acids in multi-step synthetic routes (Scheme 31). The action of these compounds on the short-chain fatty acid receptors FFA2/GPR43 and FFA3/GPR41 was studied, in addition to evaluating their activity against hydroxy-carboxylic acid receptor HCA2/GPR109A.…”