title: 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,N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a,2b,2c),N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl₃-induced model. Among them, 7.5 mg/kg of2bwas able to significantly reduce the incidence of VF induced by CHCl₃ (p< 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl₂ (p< 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p< 0.01). Therefore,2bshowed remarkably higher antiarrhythmic activity and a lower toxicity (LD50= 59.62 mg/kg, mice), simultaneously, indicating that2bcould 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,N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. huiwang2016@sina.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. chengxin920@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. kongshujun1@126.com.
authors.forename: Shujun
authors.initials: S
authors.lastname: Kong
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. yangzixian2@126.com.
authors.forename: Zixian
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. 15198906044@163.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. 15912165160@163.com.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. lijingyu06@163.com.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. guoke10141@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics Science, School of Chinese Materia Medica, Yunnan University of Traditional Chinese Medicine, 1076#, Yuhua road, Chenggong, Kunming 650000, China. yunshuma2@126.com.
authors.forename: Yunshu
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000470:Alkaloids / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D001060:Aporphines / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D017609:Barium Compounds / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D002712:Chlorides / Q000633:toxicity; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D001060:Aporphines; D017609:Barium Compounds; D002712:Chlorides; D044005:Tetrahydroisoquinolines; C024986:barium chloride; C061009:crebanine; C030168:isocorydine; C054160:stephanine; C030171:dehydrostephanine; D002251:Carbon Tetrachloride
keywords: 10,11-dibromocrebanine; 3-bromocrebanine; antiarrhythmia; aporphine derivatives; crebanine; stephanine