Novel 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazolines: Synthesis, selectively analgesic action, and QSAR analysis

Based on the knowledge that imidazoline can result in analgesic action due to its selective binding with the prostacyclin receptor, 20 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazolines (3a–t) were prepared in moderate yields. At 0.13 mmol/kg dose, their in vivo analgesic activities were evaluated after the mice were administered at 30, 60, 90, and 150 min. Compared with the pain threshold (12.27 ± 9.56–17.71 ± 7.00%) of normal saline (NS) receiving mice, the pain threshold (23.42 ± 8.14% to 102.58 ± 10.66%) of 3a–t receiving mice increases significantly. Considering a prostacyclin receptor targeting analgesic agent usually had bleeding action and to appraise the bleeding risk, the in vivo tail bleeding time of 1.30 mmol/kg 3a–t receiving mice was found to be ranged from 116.3 ± 8.2 s to 120.3 ± 9.2 s, which was substantially equal to that (117.8 ± 8.4 s to 119.0 ± 8.6 s) of NS receiving mice. Based on the possibility of imidazoline acting as vasodilator, the in vitro vasorelaxations of 3a–t were tested using the rat aortic strip model. When the aortic strip contracted by noradrenaline (NE, final concentration 10−7 mol/l) was treated with 3a–t (final concentration 5 × 10−4 mol/l), only lower percentage inhibitions (6.55 ± 5.70–37.40 ± 4.07%) were recorded, implying that the vasorelaxation of 3a–t was neglectable. By selecting appropriate molecular descriptors generated from e-dragon server, the QSAR model of the analgesic activities of 3a–t was constructed using the multiple linear regression method. The established QSAR model showed reasonable accuracy and thus it is promising to be used for screening new 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazoline derivatives as analgesic agents.

Twenty novel 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazolines (3a–t) were synthesized and characterized as analgesic agents. The preparation, in vivo evaluation, and QSAR analysis of 3a–t were reported.Figure optionsDownload as PowerPoint slide