中枢解胆碱能抗晕动病新药盐酸苯环壬酯(英文)

东莨菪碱是当前抗晕动病最强的单药,但有明显的不良反应。根据“抗胆碱药的中枢解胆碱能活性大小并不与其不良反应相平行”的假设,作者设计、合成了一系列氮杂双环醇的羧酸酯类化合物。其中由α-苯基-α-环戊基-α-羟基乙酸甲酯与N-甲基-3-氮杂双环(3 ,3 ,1)壬-9α-醇的酯交换反应制得的盐酸苯环壬酯在动物模型上,等效抗晕剂量时,其不良反应较中枢解胆碱能抗晕动病药东莨菪碱和地芬尼多为轻。临床试验表明,志愿者口服该药(每人2 ~4 mg)后,其预防晕车晕船的总有效率显著高于安慰剂对照组和阳性对照药地芬尼多组(口服每人25 ~50 mg)。在转椅致晕动症的志愿者自身对照试验中,苯环壬酯和地芬尼多都能显著减少旋转引起的眼电震图和胃电图异常改变。在另一组自身对照的旋转致晕动症人体试验中,苯环壬酯和东莨菪碱都能明显减少旋转引起的胃电活动异常,减少急性晕动病的Graybiel得分和抑制视-前庭-内耳反应。苯环壬酯每人2和4 mg的效用相当于东莨菪碱每人0 .3和0 .6 mg的效用。在易感空晕病的飞行学员中,苯环壬酯(每人3 mg)明显缩短习服空晕病所需的时间,并且在停药后其习服水平没有明显下降。苯环壬酯的不良反应主要是轻度口干(发生率9 .7 %)和轻度思睡(9 .97 %,仅发生于晕车晕船试验中)。苯环壬酯是一个中枢解胆碱能抗晕动病新药,较地芬尼多和东莨菪碱抗晕效果更好,中枢不良反应更低。

A new central anticholinergic anti-motion sickness drug phencynonate hydrochloride

At present scopolamine is the most powerful single anti-motion sickness drug, but with prominent unwanted side effects. Many attempts had been made to decrease the unwanted side effects, but no any approach was considered to be successful. Based on our working hypothesis that central cholinolytic activity of anticholinergics may not be parallel completely to their side effects, a series of alicyclic amino alcohol esters were designed, synthesized and evaluated. One of the best compounds, phencynonate HCl, was obtained by transesteration of methyl α-phenyl-α-cyclopentyl-α-hydroxy acetate with N-methyl-3-azabicyclo(3,3,1)nonan-9α-ol. In animal models it was demonstrated that at equivalent anti-motion sickness dose the side effects of phencynonate were milder than those of two other central anticholinergic anti-motion sickness drugs scopolamine HBr and difenidol HCl. In clinical trials the overall effectiveness rates for prevention of seasickness and carsickness of phencynonate (oral 2-4 mg/person) was very significantly higher than that of placebo, and also significantly higher than that of difenidol (oral 25-50 mg/person). In self controlled rotatory chair experiments in hospital laboratory, the preventive effects of phencynonate and difenidol in reducing the changes in electronystagmus and electrogastrogram were statistically significant. In another self controlled rotation experiment, phencynonate (2-4 mg/person) and scopolamine (0.3-0.6 mg/person) showed significant anti-motion sickness effects in reducing the gastric electric cycles of electrogastrogram and the Graybiel scores of acute motion sickness and significant inhibitory effects on visual-vestibular interaction dose-dependently. The anti-motion sickness effects of phencynonate 2 and 4 mg were correspondent with those of scopolamine 0.3 and 0.6 mg, respectively. Student pilots with high susceptibility to airsickness were stimulated by Coriolis acceleration. The course of desensitization and habituation to airsickness training in phencynonate group (3 mg/person) was significantly shorter than that of placebo. There was no rebounding in sensitivity to Coriolis stimulation after discontinuing phencynonate, which was reported in case of scopolamine. The side effects of phencynonate HCl were mild dry mouth (9.7%) and drowsiness (9.97%). The incidence of drowsiness is significantly lower than that of difenidol. The side effect of drowsiness was only appeared in aboard ship and bus experiments, but not in PhaseⅠ trial in hospital or in laboratory rotation tests. The incidence of drowsiness of phencynonate was also lower than that of dramamine in aboard tank experiment. Phencynonate could effectively control the acute attack of vertigo, especially Meniere′s disease and positional vertigo. In animal models of Parkinson′s disease and parkinsonism, phencynonate showed morepotent antagonistic effects than clinical common used trihexyphendyl. In summary, phencynonate is a new central anticholinergic anti-motion sickness drug with higher efficacy and lower central inhibitory side effect than difenidol and scopolamine in prevention of motion sickness. Phencynonate HCl was approved on Dec 25,1993 by State Food and Drug Administration of China as a Class Ⅰ new drug for the prevention and treatment of motion sickness in the market in China.