Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity

Abstract

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, <i>N</i>-acetamidesecocrebanine (<b>1d</b>), three bromo-substituted products of crebanine (<b>2a</b>, <b>2b</b>, <b>2c</b>), <i>N</i>-methylcrebanine (<b>2d</b>), and dehydrostephanine (<b>4a</b>) displayed antiarrhythmic effects in the CHCl₃-induced model. Among them, 7.5 mg/kg of <b>2b</b> was able to significantly reduce the incidence of VF induced by CHCl₃ (<i>p</i> < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl₂ (<i>p</i> < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (<i>p</i> < 0.01). Therefore, <b>2b</b> showed remarkably higher antiarrhythmic activity and a lower toxicity (LD₅₀ = 59.62 mg/kg, mice), simultaneously, indicating that <b>2b</b> 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, <i>N</i>-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.