title: Potent heterocyclic ligands for human complement c3a receptor.
abstract: 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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.forename: Mei-Kwan
authors.initials: MK
authors.lastname: Yau
authors.forename: Ranee
authors.initials: R
authors.lastname: Singh
authors.forename: Johan K
authors.initials: JK
authors.lastname: Hamidon
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stoermer
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D060326:Chemistry Techniques, Synthetic; D005786:Gene Expression Regulation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D011951:Receptors, Complement / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000276:Adjuvants, Immunologic; D001559:Benzhydryl Compounds; D006571:Heterocyclic Compounds; D008024:Ligands; D011951:Receptors, Complement; C431907:SB 290157; C085567:complement C3a receptor; D001120:Arginine; D002118:Calcium