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 (IC 50 μM), was transformed here into potent agonists (EC 50 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, EC 50 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.
CITATION STYLE
Reid, R. C., Yau, M. K., Singh, R., Hamidon, J. K., Lim, J., Stoermer, M. J., & Fairlie, D. P. (2014). Potent heterocyclic ligands for human complement C3a receptor. Journal of Medicinal Chemistry, 57(20), 8459–8470. https://doi.org/10.1021/jm500956p
Mendeley helps you to discover research relevant for your work.