Functional N‐Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation‐Associated Oxidative Stress

Abstract

Formyl peptide receptor-2 (FPR2) is a G protein-coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from lead compounds previuosly identified in our laboratories, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism to antagonism and to develop new FPR2 antagonists. Although none of the compounds behaved as antagonist, some of the compounds were able to induce receptor desensitization, thus functionally behaving as antagonists. Evaluation of these compounds in an in vitro model of neuroinflammation showed that they reduced reactive oxygen species (ROS) production in mouse microglial N9 cells after stimulation with lipopolysaccharide (LPS). These FPR2 ligands may protect cells from damage due to inflammation-associated oxidative stress.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders

“…Agonist activity of the target compounds at FPR1 and FPR2 was assessed by measuring their ability to induce Ca 2+ mobilization in HL-60 cells stably transfected with human FPR1 or FPR2 and was expressed as EC 50 (Table 1). Moreover, considering that both receptors are known to undergo homologous desensitization after stimulation with agonists 14 and that this can result in a functional antagonism, 30 we also assessed the ability of the compounds to induce functional antagonism at FPR1 and FPR2 by measuring the inhibition of Ca 2+ mobilization induced by subsequent treatment with FPR1 or FPR2 standard agonists (IC 50 , Table 1).…”

“…1 H NMR (CDCl 3 , 300 MHz) δ: 1.74 (s, 6H), 7.12 (m, 2H), 7.28 (m, 2H). GC/MS m/z: 164 (M + , +1, 5), 163 (M + , 27), 148 (100), 121 (30).…”

Allicin Attenuated Advanced Oxidation Protein Product-Induced Oxidative Stress and Mitochondrial Apoptosis in Human Nucleus Pulposus Cells

“…Once cellular redox homeostasis is disrupted, proteins in this environment are prone to be damaged under oxidative stress [ 12 – 14 ]. Advanced oxidation protein products (AOPP), which are important derivatives of such damaged proteins, mainly originate from oxidatively modified albumin and have been identified recently as circulating plasma biomarkers of oxidation stress [ 15 ].…”

Formyl Peptide Receptor 2 Activation Ameliorates Dermal Fibrosis and Inflammation in Bleomycin-Induced Scleroderma

“…Another possible mechanism associated with the Fpr2-mediated immune resolution is receptor desensitization, which plays a key role in the regulation of G protein-coupled receptor signaling and trafficking (30). Recent studies have demonstrated that FPR2 agonists, lipoxin A4 and some of ureidopropanamide derivatives, induced FPR2 internalization and desensitization (25, 31). Moreover, it has been reported that compound 43, a non-peptidyl agonist for mouse Fpr1 and Fpr2, inhibited neutrophil migration in mice by inducing cross-desensitization of CXCR2, a chemoattractant receptor (32).…”