Title |
Potent Heterocyclic Ligands for Human Complement C3a Receptor
|
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Published in |
Journal of Medicinal Chemistry, October 2014
|
DOI | 10.1021/jm500956p |
Pubmed ID | |
Authors |
Robert C. Reid, Mei-Kwan Yau, Ranee Singh, Johan K. Hamidon, Junxian Lim, Martin J. Stoermer, David P. Fairlie |
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. |
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Geographical breakdown
Country | Count | As % |
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Germany | 1 | 3% |
Unknown | 36 | 95% |
Demographic breakdown
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Researcher | 19 | 50% |
Student > Ph. D. Student | 5 | 13% |
Student > Master | 4 | 11% |
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Lecturer > Senior Lecturer | 1 | 3% |
Other | 1 | 3% |
Unknown | 6 | 16% |
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Psychology | 1 | 3% |
Other | 2 | 5% |
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