FPR2 and brimstone: a novel approach for the treatment of neuroinflammation

Neurodegenerative diseases like Parkinson’s Disease and Alzheimer’s Disease involve several pathological phenomena that result in a diffuse neuroinflammatory state, exacerbating tissue damage via oxidative stress. Neuroinflammation is a multifaceted pathological factor involving several cell types, receptors, and mediators, and its resolution could help alter disease progression1. Formyl Peptide Receptor 2 (FPR2) is a G protein-coupled receptor (GPCR) expressed in microglia. It controls several aspects of the immune response and could thus be a key target for the resolution of neuroinflammation. Our research efforts have resulted in developing the ureidopropanamide class of FPR2 agonists2. We have set out to enhance the anti-inflammatory capabilities of these compounds by incorporating an H2S-releasing moiety into their scaffold. H2S is a gaseous neuromodulator and neuroprotector, regulating calcium influx and exerting anti-inflammatory and antioxidant effects at low doses3. Thus, the ureido and amide moieties of our compounds were converted into the corresponding thioureas or thioamides. Figure 1: scaffolds of ureidopropanamide FPR2 agonists and their thioureido and thioamide counterparts. These compounds were tested as FPR2 agonists, for their capacity as H2S releasers, and their neuroprotective activity in models of neuroinflammation, showing a promising activity profile and demonstrating their potential as lead compounds for a new generation of anti-neuroinflammatory drugs.