Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA.
Department of Pharmacology and Toxicology, College of Veterinary Medicine, University of Belgrade, Belgrade, Serbia.
Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):36-42. doi: 10.1016/j.ijpddr.2017.12.001. Epub 2017 Dec 16.
Zolvix is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum) comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC values: 1.6 ± 3.1 nM and 0.2 ± 2.3 μM). We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes.
左维昔是一种最近引入的驱虫滴剂，其有效成分是莫能菌素。莫能菌素是几种线虫属种中 DEG-3/DES-2 型烟碱型乙酰胆碱受体（nAChR）的正变构调节剂。据报道，该药会导致秀丽隐杆线虫和捻转血矛线虫体肌过度收缩。我们研究了莫能菌素对异源表达于非洲爪蟾卵母细胞中的猪蛔虫和食道口线虫 nAChR 的影响。我们使用双电极电压钳电生理学研究了莫能菌素对由 ACR-16 组成的尼古丁偏好同型 nAChR 亚基的影响；对由 UNC-29、UNC-38 和 UNC-63 亚基组成的吡喹酮/噻嘧啶偏好异型亚基的影响；以及由 UNC-29、UNC-38、UNC-63 和 ACR-8 亚基组成的左旋咪唑偏好亚基（食道口线虫）的影响。对于每种测试的亚型，单独使用莫能菌素均未产生可测量的电流，从而排除了激动剂作用。当莫能菌素连续应用时，它以浓度依赖的方式降低乙酰胆碱诱导电流的幅度。在所有三种亚型中，莫能菌素均为表达受体的非竞争性拮抗剂。猪蛔虫的 ACR-16 对莫能菌素抑制特别敏感（IC 值：1.6 ± 3.1 nM 和 0.2 ± 2.3 μM）。我们还研究了莫能菌素对成年猪蛔虫分离的肌肉瓣的影响。单独应用该药时，对基础张力无明显影响。与异源表达受体中的乙酰胆碱诱导电流一样，莫能菌素拮抗乙酰胆碱诱导的收缩。进一步的研究表明，抑制作用是竞争和非竞争拮抗的混合物。我们的发现表明，莫能菌素对多种 nAChR 亚型均具有活性。
