title: Novel 1-oxyl-2-substitutedphenyl-4,4,5,5-tetramethylimidazolines: synthesis, selectively analgesic action, and QSAR analysis.
abstract: 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+/-8.2s to 120.3+/-9.2s, which was substantially equal to that (117.8+/-8.4s to 119.0+/-8.6s) 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 x 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.
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University, Beijing 100054, 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: D000465:Algorithms; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048288:Imidazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009126:Muscle Relaxation / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D044006:Receptors, Epoprostenol / Q000187:drug effects / Q000378:metabolism; D012044:Regression Analysis; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000700:Analgesics; D048288:Imidazolines; D007202:Indicators and Reagents; D044006:Receptors, Epoprostenol; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009638:Norepinephrine