Wolstenholme Adrian J
Dept. of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, USA.
Int J Parasitol Drugs Drug Resist. 2011 Oct 14;1(1):2-13. doi: 10.1016/j.ijpddr.2011.09.003. eCollection 2011 Dec.
Many of the anthelmintic drugs in use today act on the nematode nervous system. Ion channel targets have some obvious advantages. They tend to act quickly, which means that they will clear many infections rapidly. They produce very obvious effects on the worms, typically paralyzing them, and these effects are suitable for use in rapid and high-throughput assays. Many of the ion channels and enzymes targeted can also be incorporated into such assays. The macrocyclic lactones bind to an allosteric site on glutamate-gated chloride channels, either directly activating the channel or enhancing the effect of the normal agonist, glutamate. Many old and new anthelmintics, including tribendimidine and the amino-acetonitrile derivatives, act as agonists at nicotinic acetylcholine receptors; derquantel is an antagonist at these receptors. Nematodes express many different types of nicotinic receptor and this diversity means that they are likely to remain important targets for the foreseeable future. Emodepside may have multiple effects, affecting both a potassium channel and a pre-synaptic G protein-coupled receptor; although few other current drugs act at such targets, this example indicates that they may be more important in the future. The nematode nervous system contains many other ion channels and receptors that have not so far been exploited in worm control but which should be explored in the development of effective new compounds.
当今使用的许多驱虫药物作用于线虫神经系统。离子通道靶点具有一些明显的优势。它们往往起效迅速，这意味着它们能快速清除许多感染。它们对线虫产生非常明显的作用，通常会使其麻痹，而且这些作用适用于快速和高通量检测。许多被靶向的离子通道和酶也可纳入此类检测。大环内酯类药物与谷氨酸门控氯离子通道上的变构位点结合，要么直接激活该通道，要么增强正常激动剂谷氨酸的作用。许多新旧驱虫药，包括三苯双脒和氨基乙腈衍生物，在烟碱型乙酰胆碱受体上作为激动剂起作用；地喹特是这些受体的拮抗剂。线虫表达许多不同类型的烟碱型受体，这种多样性意味着在可预见的未来它们可能仍然是重要的靶点。埃玛菌素可能有多种作用，影响一种钾通道和一种突触前G蛋白偶联受体；尽管目前很少有其他药物作用于此类靶点，但这个例子表明它们在未来可能会更重要。线虫神经系统包含许多其他离子通道和受体，目前在蠕虫防治中尚未得到利用，但在开发有效的新化合物时应加以探索。
