Potent Heterocyclic Ligands for Human Complement C3a Receptor

The G-protein coupled receptor (C3aR) for human inflammatory protein complement C3a is an important component of immune, inflammatory, and metabolic diseases. A flexible compound (<i>N</i>2-[(2,2-diphenylethoxy)­acetyl]-l-arginine, <b>4</b>), known as a weak C3aR antagonist (IC₅₀ μM), was transformed here into potent agonists (EC₅₀ nM) of human macrophages (Ca²⁺ release in HMDM) by incorporating aromatic heterocycles. Antagonists were also identified. A linear correlation between binding affinity for C3aR and calculated hydrogen-bond interaction energy of the heteroatom indicated that its hydrogen-bonding capacity influenced ligand affinity and function mediated by C3aR. Hydrogen-bond accepting heterocycles (e.g., imidazole) conferred the highest affinity and agonist potency (e.g., <b>21</b>, EC₅₀ 24 nM, Ca²⁺, HMDM) with comparable efficacy and immunostimulatory activity as that of C3a in activating human macrophages (Ca²⁺, IL1β, TNFα, CCL3). These potent and selective modulators of C3aR, inactivated by a C3aR antagonist, are stable C3a surrogates for interrogating roles for C3aR in physiology and disease