Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl₃, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl₂. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, -acetamidesecocrebanine (), three bromo-substituted products of crebanine (, ,), -methylcrebanine (), and dehydrostephanine () displayed antiarrhythmic effects in the CHCl₃-induced model. Among them, 7.5 mg/kg of was able to significantly reduce the incidence of VF induced by CHCl₃ ( < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl₂ ( < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min ( < 0.01). Therefore, showed remarkably higher antiarrhythmic activity and a lower toxicity (LD = 59.62 mg/kg, mice), simultaneously, indicating that could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation,-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.
