Potent heterocyclic ligands for human complement c3a receptor.
J Med Chem
; 57(20): 8459-70, 2014 Oct 23.
Article
in En
| MEDLINE
| ID: mdl-25259874
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+), IL1ß, 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Complement
/
Heterocyclic Compounds
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2014
Document type:
Article
Affiliation country:
Australia