- A new class of analgesic agents toward prostacyclin receptor inhibition: Synthesis, biological studies and QSAR analysis of 1-hydroxyl-2-substituted phenyl-4,4,5,5-tetramethylimidazolines
-
By studying the structural similarity of analgesic imidazolines and 2-phenylnitronyl nitroxides, 20 1-hydroxyl-2-substituted phenyl-4,4,5,5-tetramethylimidazolines (2a-t) were newly synthesized as selective antagonists of prostacyclin receptor (IP receptor). In the in vivo tail-flick assay, 2a-t (dose, 0.13 mmol/kg) receiving mice showed increased pain thresholds ranging from 20.52 ± 7.25% to 90.94 ± 11.97%, which were significantly higher than that ranged from 12.27 ± 9.56% to 17.71 ± 7.00% shown by normal saline (NS) receiving mice. In the in vivo tail bleeding assay, 2a-t (dose, 1.30 mmol/kg) receiving mice gave a bleeding time ranging from 116.3 ± 8.0 s to 119.6 ± 7.1 s, and NS receiving mice gave a bleeding time ranging from 116.7 ± 7.5 s to 119.1 ± 8.7 s, which were at a substantially equal level. These observations imply that no bleeding risk occurred even when 10-fold dose of analgesic assay was used. In the in vitro vasorelaxation assay, it was found that when the aortic strip contracted by noradrenaline (NE, final concentration, 10-7 M) was treated with the solution of 2a-t in NS (final concentration, 5 × 10-3 M) only lower percentage inhibitions ranged from 6.63 ± 2.72% to 46.28 ± 2.63% were recorded. Relatively higher concentration of 2a-t (5 × 10-3 M) and relatively lower percentage inhibitions (13 of 20 less than 23.27 ± 3.47%) suggest that 2a-t exhibit few vasodilation activity. To shed some light on the potential analgesic mechanisms of 2a-t, moreover, a QSAR analysis was carried out by using the multiple linear regression method. Taken altogether, the current study confirms that as selective antagonist of IP receptor 1-hydroxyl-2-substituted phenyl-4,4,5,5-tetramethylimidazoline may be a promising lead compound of analgesic agent without cardiovascular and bleeding side effects.
- Zhao, Ming,Li, Zheng,Peng, Li,Tang, Yu-Rong,Wang, Chao,Zhang, Ziding,Peng, Shiqi
-
p. 1048 - 1058
(2008/09/20)
-
- 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.
- Zhao, Ming,Li, Zheng,Peng, Li,Tang, Yu-Rong,Wang, Chao,Zhang, Ziding,Peng, Shiqi
-
p. 2815 - 2826
(2007/10/03)
-
- Novel 2-substituted nitronyl nitroxides as free radical scavengers: Synthesis, biological evaluation and structure-activity relationship
-
To develop more potent small molecules with enhanced free radical scavenger properties, we designed and synthesized a series of nitronyl nitroxide derivatives 4a-h. A lead compound 4f was discovered based on Ach-induced vascorelaxation assay. Further chemical modification based on this scaffold provided a new series of 2-substituted phenylnitronyl nitroxide derivatives 6a-s. The newly synthesized compounds 6a-s possess improved radical scavenger's activity based on PC12 cell survival assay. Compounds 6g,n,o, and s are some of the most potent compounds in terms of NO, H2O2, and OH scavenging ability. 2-Substitued phenylnitronyl nitroxides had a higher radical scavenging activity with the electron-donating group (EDG). In contrast, the introduction of electron-withdrawing group (EWG) to the aromatic ring led to a dramatic decrease in its radical scavenging activity. These results suggest that the electron-donating group (EDG) of the aromatic ring may be an important factor influencing the radical scavenging behavior of these compounds, and the potency of free radical scavenging activity largely depended on the position and electronic properties of the phenyl ring substituents. The enhanced radical scavenging capacities of the novel 2-substituted nitronyl nitroxides may be potential drug leads against the deleterious action of ROS (reactive oxygen species)/RNS (reactive nitrogen species).
- Wu, Yihui,Bi, Lanrong,Bi, Wei,Li, Zeng,Zhao, Ming,Wang, Chao,Ju, Jingfang,Peng, Shiqi
-
p. 5711 - 5720
(2007/10/03)
-