Potent heterocyclic ligands for human complement C3a receptor

Reid, Robert C., Yau, Mei-Kwan, Singh, Ranee, Hamidon, Johan K., Lim, Junxian, Stoermer, Martin J. and Fairlie, David P. (2014) Potent heterocyclic ligands for human complement C3a receptor. Journal of Medicinal Chemistry, 57 20: 8459-8470. doi:10.1021/jm500956p

Author Reid, Robert C.
Yau, Mei-Kwan
Singh, Ranee
Hamidon, Johan K.
Lim, Junxian
Stoermer, Martin J.
Fairlie, David P.
Title Potent heterocyclic ligands for human complement C3a receptor
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
Publication date 2014-10-23
Sub-type Article (original research)
DOI 10.1021/jm500956p
Open Access Status
Volume 57
Issue 20
Start page 8459
End page 8470
Total pages 12
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2015
Language eng
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 (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., 21, 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Created: Thu, 13 Nov 2014, 12:20:26 EST by Dr Robert Reid on behalf of Institute for Molecular Bioscience