Evaluation of Sedative-Hypnotic effects of novel 2-colrobenzyloxi 4, 6-diphenylpyrimidin-2-ol in experimental animal models

Introduction: Benzodiazepines (BDZs) are used as psychoactive drugs in current medicine and has been introduced to medical practice since 1960. The pharmacological effects of benzodiazepines (BZDs) make them the most important GABA-A receptor modulating drugs, which are currently used in clinic. They act by potentiating GABA induced Cl- currents. However, BDZs are the safest psychoactive drugs available today, although they have some adverse effects‚ including dependence‚ cognitive impairment and ataxia. New BZD receptor ligands with more selective effects such as anti-anxiety, anti-seizure and fewer adverse drug reactions were synthesized in the last two decades. According to SAR of BZDs agonists, novel 4,6-diphenylpyrimidin-2-ol derivatives were designed and synthesized. In this study the sedative-hypnotic effect of one of this novel compound, (4-(2-((2-chlorobenzyl)oxy)phenyl)-6-(4-chlorophenyl)pyrimidin-2-ol), was evaluated in mice using experimental tests.Methods: The experiments were conducted on 40 male NMRI mice (n=8 in all group). The sedative-hypnotic effect of the novel compound was assessed by pentobarbital induced sleeping test. After pre-treatment of different doses of the novel compound (5, 10, 20, 40 mg/kg), animals will receive I.P injection of sodium pentobarbital at a dose of 40 mg/kg. Following pentobarbital injection, each mouse will be observed for onset of sleep (loss of righting reflex). The time between loss (sleep onset) and recovery of the righting reflex should be measured.Result: The results showed that, the novel compound at doses of 20 and 40 mg/kg significantly (p<0.001 and p<0.001 respectively) increased the sleeping time induced by pentobarbital compared to the control group.Conclusion: We conclude that the novel compound, 4-(2-((2-chlorobenzyl)oxy)phenyl)-6-(4-chlorophenyl)pyrimidin-2-ol, may have sedative-hypnotic activates and increase duration of the loss of righting reflex in the pentobarbital-induced sleeping test. However, further studies are necessary to find other activates of the novel compound and its mechanism of action.

Keywords:

Novel 4 , 6-diphenylpyrimidin-2-ol derivatives , Pentobarbital induced sleeping test , sedative , hypnotic , mice