Potent heterocyclic ligands for human complement c3a receptor

J Med Chem. 2014 Oct 23;57(20):8459-70. doi: 10.1021/jm500956p. Epub 2014 Oct 8.


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 (N2-[(2,2-diphenylethoxy)acetyl]-l-arginine, 4), known as a weak C3aR antagonist (IC50 μM), was transformed here into potent agonists (EC50 nM) of human macrophages (Ca(2+) 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., 21, EC50 24 nM, Ca(2+), HMDM) with comparable efficacy and immunostimulatory activity as that of C3a in activating human macrophages (Ca(2+), 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology
  • Arginine / analogs & derivatives
  • Arginine / chemistry
  • Arginine / pharmacology
  • Benzhydryl Compounds / chemistry
  • Benzhydryl Compounds / pharmacology
  • Calcium / metabolism
  • Cells, Cultured
  • Chemistry Techniques, Synthetic
  • Gene Expression Regulation / drug effects
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Receptors, Complement / agonists*
  • Receptors, Complement / antagonists & inhibitors
  • Receptors, Complement / metabolism*
  • Structure-Activity Relationship


  • Adjuvants, Immunologic
  • Benzhydryl Compounds
  • Heterocyclic Compounds
  • Ligands
  • Receptors, Complement
  • SB 290157
  • complement C3a receptor
  • Arginine
  • Calcium