Potent Heterocyclic Ligands for Human Complement C3a Receptor

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• 作者：Robert C. Reid ; Mei-Kwan Yau ; Ranee Singh ; Johan K. Hamidon ; Junxian Lim ; Martin J. Stoermer ; David P. Fairlie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8459-8470
• 全文大小：545K
• ISSN：1520-4804

文摘

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 渭M), 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⁺, IL1尾, TNF伪, 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.