Aspirin metabolites are GPR35 agonists

Deng, Huayun; Ye, Fang

doi:10.1007/s00210-012-0752-0

Cited by 20 publications

(12 citation statements)

References 34 publications

(47 reference statements)

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“…37 Acetylsalicylic acid is converted to salicylic acid and conjugates with benzoic acid in the liver to result in the synthesis of hippuric acid. The other major metabolites of aspirin include salicyluric acid and gentisuric acid which have very similar structural moieties as hippuric acid.…”

Section: Discussionmentioning

confidence: 99%

The ex vivo antiplatelet activation potential of fruit phenolic metabolite hippuric acid

2015

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Polyphenol-rich fruit and vegetable intake has been associated with reduction in platelet hyperactivity, a significant contributor to thrombus formation. This study was undertaken to investigate the possible role of hippuric acid, a predominant metabolite of plant cyclic polyols, phenolic acids and polyphenols, in reduction of platelet activation-related thrombogenesis. Fasting blood samples were collected from 13 healthy subjects to analyse the effect of varying concentrations of hippuric acid (100 μM, 200 μM, 500 μM, 1 mM and 2 mM) on activation-dependant platelet surface-marker expression. Procaspase activating compound-1 (PAC-1) and P-selectin/CD62P monoclonal antibodies were used to evaluate platelet activation-related conformational changes and α-granule release respectively using flow cytometry. Platelets were stimulated ex vivo via the P2Y1/P2Y12- adenosine diphosphate (ADP) pathway of platelet activation. Hippuric acid at a concentration of 1 mM and 2 mM significantly reduced P-selectin/CD62P expression (p = 0.03 and p < 0.001 respectively) induced by ADP. Hippuric acid at 2 mM concentration also inhibited PAC-1 activation-dependant antibody expression (p = 0.03). High ex vivo concentrations of hippuric acid can therefore significantly reduce P-selectin and PAC-1 expression thus reducing platelet activation and clotting potential. However, although up to 11 mM of hippuric acid can be excreted in the urine per day following consumption of fruit, hippuric acid is actively excreted with a recorded Cmax for hippuric acid in human plasma at 250-300 μM. This is lower than the blood concentration of 1-2 mM shown to be bioactive in this research. The contribution of hippuric acid to the protective effects of fruit and vegetable intake against vascular disorders by the pathways measured is therefore low but could be synergistic with lowered doses of antiplatelet drugs and help reduce risk of thrombosis in current antiplatelet drug sensitive populations.

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Section: Discussionmentioning

confidence: 99%

The ex vivo antiplatelet activation potential of fruit phenolic metabolite hippuric acid

2015

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“…However, its use to define the biology of GPR35 is limited by its known action as a PDE V and VI inhibitor (Taniguchi et al, 2006). Moreover, other recently reported GPR35 agonists, although of reasonable potency, have been identified predominantly via screens of small libraries of known, pharmacologically relevant, drugs (Jenkins et al, 2010;Zhao et al, 2010) and/or have known activity at other targets (Yang et al, 2010(Yang et al, , 2012Deng and Fang, 2012;Deng et al, 2012a,b;Hu et al, 2012). Furthermore, certain of these ligands, including the currently described antagonists, display markedly different affinity at human and rodent orthologs of GPR35 (Jenkins et al, 2010(Jenkins et al, , 2012, limiting their potential to define the function of GPR35 in rodent models and in cells derived from these species.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Identification and Characterization of Novel, Species-selective GPR35 Agonists

Neetoo-Isseljee

Mackenzie

Southern

et al. 2012

J Pharmacol Exp Ther

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Drugs targeting the orphan receptor GPR35 have potential therapeutic application in a number of disease areas, including inflammation, metabolic disorders, nociception, and cardiovascular disease. Currently available surrogate GPR35 agonists identified from pharmacologically relevant compound libraries have limited utility due to the likelihood of off-target effects in vitro and in vivo and the variable potency that such ligands exhibit across species. We sought to identify and characterize novel GPR35 agonists to facilitate studies aimed at defining the physiologic role of GPR35. PathHunter b-arrestin recruitment technology was validated as a human GPR35 screening assay, and a high-throughput screen of 100,000 diverse low molecular weight compounds was conducted. Confirmed GPR35 agonists from five distinct chemotypes were selected for detailed characterization using both b-arrestin recruitment and G proteindependent assays and each of the human, mouse, and rat GPR35 orthologs. These studies identified 4-{(Z)-[(2Z)-2-(2-fluorobenzylidene)-4-oxo-1,3-thiazolidin-5-ylidene]methyl}benzoic acid (compound 1) as the highest potency full agonist of human GPR35 yet described. As with certain other GPR35 agonists, compound 1 was markedly selective for human GPR35, but displayed elements of signal bias between b-arrestin-2 and G protein-dependent assays. Compound 1 also displayed competitive behavior when assessed against the human GPR35 antagonist, ML-145 (2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid). Of the other chemotypes studied, compounds 2 and 3 were selective for the human receptor, but compounds 4 and 5 demonstrated similar activity at human, rat, and mouse GPR35 orthologs. Further characterization of these compounds and related analogs is likely to facilitate a better understanding of GPR35 in health and disease.

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“…This approach was taken by Mackenzie et al (2014) , who used the differences in species selectivity at GPR35 to identify residues involved in ligand function. Based on the knowledge that the majority of GPR35 ligands contain at least one carboxyl group ( Jenkins et al, 2010 ; Deng et al, 2011b , 2012b ; Deng and Fang, 2012 ; Funke et al, 2013 ; Thimm et al, 2013 ), or a bioisostere of a carboxyl group ( Mackenzie et al, 2014 ), it was postulated that positively charged residues within the generic ligand binding pocket of GPR35 that differed between human and rat might mediate the differences in potency. To this end, “species swap” mutations were carried out to switch key arginine residues positioned within proposed ligand binding regions ( Venkatakrishnan et al, 2013 ) to the equivalent non-arginine residue in the opposite species ortholog.…”

Section: Receptor Homology Modeling Efforts Indicate That the Bindingmentioning

confidence: 99%

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

et al. 2015

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G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target.

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Aspirin metabolites are GPR35 agonists

Cited by 20 publications

References 34 publications

The ex vivo antiplatelet activation potential of fruit phenolic metabolite hippuric acid

The ex vivo antiplatelet activation potential of fruit phenolic metabolite hippuric acid

High-Throughput Identification and Characterization of Novel, Species-selective GPR35 Agonists

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

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