title: 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.
abstract: 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+/-7.5s to 119.1+/-8.7s, 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 x 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 x 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.
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Tang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Ziding
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D006470:Hemorrhage / Q000139:chemically induced; D048288:Imidazolines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D016014:Linear Models; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement; D017288:Pain Threshold; D021281:Quantitative Structure-Activity Relationship; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors*; D013623:Tail / Q000098:blood supply; D014664:Vasodilation / Q000187:drug effects