具有多种心血管保护作用的新型azulene-1-carboxamidine衍生物HNS-32的研究进展

Y. Tanaka, K. Shigenobu
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引用次数: 9

摘要

HNS-32 [N(1),N(1)-二甲基-N(2)-(2-吡啶基甲基)-5-异丙基-3,8-二甲基苄基-1- carboxamidine] (CAS注册号:186086-10-2)是一种新合成的氮杂烯衍生物。计算机模拟表明,其三维结构与Ib类抗心律失常药物如利多卡因或美西汀相似。HNS-32有效抑制狗和大鼠因冠状动脉结扎和/或缺血再灌注引起的室性心律失常。在离体犬和豚鼠心脏组织中,HNS-32具有负性肌力和变时作用,延长房室和室室传导时间,增加冠状动脉血流量。在离体豚鼠心室乳头肌中,HNS-32可降低最大动作电位上搏率(Vmax),缩短动作电位持续时间(APD)。这些发现表明HNS-32抑制向内Na+和Ca2+通道电流。在离体猪冠状动脉和兔导管动脉中,HNS-32抑制多种化学刺激诱导的Ca2+通道依赖性和非依赖性收缩。HNS-32是蛋白激酶C (PKC)介导的脑动脉收缩的有效抑制剂。它可能阻断心脏和血管平滑肌中表达的Na+和Ca2+通道。这些多离子通道阻断作用是HNS-32抗心律失常和血管松弛作用的主要原因。这种药物可能是治疗心律失常的一种新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A review of HNS-32: a novel azulene-1-carboxamidine derivative with multiple cardiovascular protective actions.
HNS-32 [N(1),N(1)-dimethyl-N(2)-(2-pyridylmethyl)-5-isopropyl-3,8-dimethylazulene-1- carboxamidine] (CAS Registry Number: 186086-10-2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS-32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia-reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS-32 had negative inotropic and chronotropic actions, prolonged atrial-His and His-ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS-32 decreased maximal rate of action potential upstroke (Vmax) and shortened action potential duration (APD). These findings suggest that HNS-32 inhibits inward Na+ and Ca2+ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS-32 inhibited both Ca2+ channel-dependent and -independent contractions induced by a wide variety of chemical stimuli. HNS-32 is a potent inhibitor of protein kinase C (PKC)-mediated constriction of cerebral arteries. It is likely to block both, Na+ and Ca2+ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS-32. This drug may represent a novel approach to the treatment of arrhythmias.
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