A subset of highly effective propafenone-type multidrug resistance modulators lacks effects on cardiac action potential and mechanical twitch parameters of rat papillary muscles
A subset of highly effective propafenone-type multidrug resistance modulators lacks effects on cardiac action potential and mechanical twitch parameters of rat papillary muscles
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DOI：
10.1124/jpet.103.052993
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发表时间：
2003-11-01
影响因子：
3.5
通讯作者：
Chiba, P
中科院分区：
文献类型：
--
作者：
Schmid, D;Staudacher, DL;Chiba, P
在这项研究中，我们测试了一系列12种先前确定的高效普罗帕酮型多药耐药（MDR）调节剂，因为它们可能对心脏组织产生不良影响。我们使用大鼠乳头肌制剂，定量测定了这些物质阻断动作电位（AP）上冲程速度（V-max）和延长APD的效力（50）。同时，对等距抽动参数的影响进行了评价。得到了各参数的浓度-响应曲线。在这些化合物的一个亚群中，我们发现阻断V-max （ki(Vmax)）和抑制多药耐药细胞中道诺霉素外排（IC50）之间存在显著的等级相关性（r' = 0.87; p < 0.05）。令人惊讶的是，大多数具有额外芳香侧链的亲脂化合物对AP和机械抽搐参数完全没有影响，尽管它们是最有效的MDR调节剂。额外的结构修饰，如芳香环的氟取代，芳基哌嗪或哌啶侧链的引入，以及修改羰基的氢键受体强度，都没有重建心脏副作用。相反，当这些物质在普罗帕酮核心结构的苯基丙烯部分被截断时，心脏效应再次发生。我们得出结论，氮原子附近的芳香取代基可能由于位阻而阻止与离子通道的相互作用，因此是消除不必要的心脏效应的先决条件。
In this study, we tested a series of 12 previously identified, highly effective propafenone-type multidrug resistance (MDR) modulators for their possible undesirable effects on cardiac tissue. We used rat papillary muscle preparations and quantitatively determined the potency of these substances to block action potential (AP) upstroke velocity (V-max) and to prolong APD(50). Simultaneously, the effects on isometric twitch parameters were evaluated. Concentration-response curves were obtained for all parameters. Within a subset of the compounds, we found a significant rank correlation (r' = 0.87; p < 0.05) between potencies to block V-max (ki(Vmax)) and to inhibit daunomycin efflux in MDR cells (IC50). Surprisingly, the most lipophilic compounds with additional aromatic side chains completely lacked effects on AP and mechanical twitch parameters, although they are the most effective MDR modulators. Additional structural modifications such as fluoride substitution of the aromatic ring, introduction of arylpiperazine or piperidine side chains, as well as modifying the hydrogen bond acceptor strength of the carbonyl group did not reestablish cardiac side effects. In contrast, when these substances were truncated at the phenylpropiophenone moiety of the propafenone core structure, cardiac effects reoccurred. We conclude that aromatic substituents in the vicinity of the nitrogen atom prevent interaction with ion channels, likely due to steric hindrance, and are thus a prerequisite for eliminating unwanted cardiac effects.