A new central anticholinergic anti-motion sickness drug phencynonate hydrochloride / 中国药理学与毒理学杂志

ABSTRACT

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.