The anthelmintic pyrantel acts as a low efficacious agonist and an open-channel blocker of mammalian acetylcholine receptors.
The anthelmintic pyrantel acts as a low efficacious agonist and an open-channel blocker of mammalian acetylcholine receptors.
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驱虫药噻嘧啶是一种低效激动剂和哺乳动物乙酰胆碱受体的开放通道阻断剂。
DOI：
10.1016/s0028-3908(01)00057-0
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发表时间：
2001
影响因子：
4.7
通讯作者：
Bouzat,C
中科院分区：
文献类型：
--
作者：
Rayes,D;DeRosa,MJ;Spitzmaul,G;Bouzat,C
噻嘧啶是一种驱虫药，作为线虫烟碱受体（AChR）的激动剂，通过使线虫肌膜去极化发挥治疗作用。在此，我们在单通道水平探索噻嘧啶对哺乳动物肌肉AChR的作用。噻嘧啶可诱发AChR电流。然而，在噻嘧啶浓度范围内（1-300 μM），开口未出现在可明确识别的簇中。平均开放时间作为浓度的函数降低，表明额外的开放通道阻滞。在高ACh浓度和噻嘧啶存在下的单通道记录表明，驱虫剂作为一种高亲和力的开放通道阻滞剂。当以顺序阻断模式分析时，计算出阻断过程的正向速率常数为8× 107 M − 1 s −1，在膜电位为−70 mV时表观解离常数为8 μM，且该过程是电压依赖性的。噻嘧啶取代α-银环蛇毒素结合，但平衡结合的浓度依赖性相对于ACh结合向更高浓度偏移。因此，通过作用于结合位点噻嘧啶以低效力激活哺乳动物AChR，并通过空间阻断孔，然后快速抑制激活的通道。
Pyrantel is an anthelmintic which acts as an agonist of nicotinic receptors (AChRs) of nematodes and exerts its therapeutic effects by depolarizing their muscle membranes. Here we explore at the single-channel level the action of pyrantel at mammalian muscle AChR. AChR currents are elicited by pyrantel. However, openings do not appear in clearly identifiable clusters over a range of pyrantel concentrations (1–300 μM). The mean open time decreases as a function of concentration, indicating an additional open-channel block. Single-channel recordings in the presence of high ACh concentrations and pyrantel demonstrate that the anthelmintic acts as a high-affinity open-channel blocker. When analyzed in terms of a sequential blocking scheme, the calculated forward rate constant for the blocking process is 8×107M−1s−1, the apparent dissociation constant is 8 μM at a membrane potential of −70 mV and the process is voltage dependent. Pyrantel displaces α-bungarotoxin binding but the concentration dependence of equilibrium binding is shifted towards higher concentrations with respect to that of ACh binding. Thus, by acting at the binding site pyrantel activates mammalian AChRs with low efficacy, and by sterical blockade of the pore, the activated channels are then rapidly inhibited.