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.

Synthetic route of 1-hydroxy-2-substituted phenyl-4,4,5,5-tetramethylimidazolines (2a–t).Figure optionsDownload as PowerPoint slide