Fig. 1
Structures and activities for human C3aR agonists and antagonists. a Chemical structures of synthetic compounds 1–6; b, c Concentration-dependent histamine secretion in human LAD2 mast cells induced by: b hC3a (EC50 3 ± 1.5 nM) vs. agonists 1 (EC50 110 ± 40 nM), 2 (EC50 300 ± 100 nM) or 3 (EC50 20 ± 10 nM) alone. c hC3a (100 nM) was inhibited by antagonist 4 (IC50 90 ± 50 nM) or 5 (IC50 40 ± 20 nM) or 6 (IC50 3.5 ± 1.5 nM). All the data n ≥ 3, error bars are ± SEM; d, e 2D ROESY 1H-NMR spectra in DMSO-d6 for 1–6. d Amide NH…aromatic CH ROE correlations (c,d and e,f labeled protons, blue boxes) for antagonists 4 and 6, but not for agonist 1 (a,b labeled protons expected in red box). e 2D ROESY 1H-NMR spectra in DMSO-d6 show amide NH…Me ROE correlations for antagonist 5 (h, g labeled protons, blue box) but not for agonists 2 and 3 (i,j or k,l labeled protons expected in red boxes). The data indicate a distinct conformational difference between agonists (1, 2, 3) and antagonists (4, 5, 6). f Energy minimized structures with electrostatic surface potential maps for agonist 3 and antagonist 6 show the respective X-C-C-O dihedral angles and dramatically different orientations of the Arg residue. Ab initio calculations (DFT B3LYP/6-311g(2d,2p)) were performed using Gaussian 09 and imaged with GaussView 5
