Zheng Fudan, Du Xiangwei, Chou Tsung-Han, Robertson Alan P, Yu Edward W, VanVeller Brett, Martin Richard J
Department of Chemistry, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
Department of Physics and Astronomy, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):12-22. doi: 10.1016/j.ijpddr.2016.12.001. Epub 2016 Dec 9.
Nematode parasites infect ∼2 billion people world-wide. Infections are treated and prevented by anthelmintic drugs, some of which act on nicotinic acetylcholine receptors (nAChRs). There is an unmet need for novel therapeutic agents because of concerns about the development of resistance. We have selected Asu-ACR-16 from a significant nematode parasite genus, Ascaris suum, as a pharmaceutical target and nicotine as our basic moiety (EC 6.21 ± 0.56 μM, I 82.39 ± 2.52%) to facilitate the development of more effective anthelmintics. We expressed Asu-ACR-16 in Xenopus oocytes and used two-electrode voltage clamp electrophysiology to determine agonist concentration-current-response relationships and determine the potencies (ECs) of the agonists. Here, we describe the synthesis of a novel agonist, (S)-5-ethynyl-anabasine, and show that it is more potent (EC 0.14 ± 0.01 μM) than other nicotine alkaloids on Asu-ACR-16. Agonists acting on ACR-16 receptors have the potential to circumvent drug resistance to anthelmintics, like levamisole, that do not act on the ACR-16 receptors.
线虫寄生虫感染了全球约20亿人。感染通过驱虫药物进行治疗和预防，其中一些药物作用于烟碱型乙酰胆碱受体（nAChRs）。由于担心耐药性的发展，对新型治疗药物存在未满足的需求。我们从重要的线虫寄生虫属猪蛔虫中选择了Asu-ACR-16作为药物靶点，并选择尼古丁作为我们的基本部分（EC 6.21±0.56μM，I 82.39±2.52%），以促进更有效的驱虫药的开发。我们在非洲爪蟾卵母细胞中表达了Asu-ACR-16，并使用双电极电压钳电生理学来确定激动剂浓度-电流-反应关系，并确定激动剂的效价（ECs）。在这里，我们描述了一种新型激动剂（S）-5-乙炔基-去甲烟碱的合成，并表明它对Asu-ACR-16的效力比其他尼古丁生物碱更强（EC 0.14±0.01μM）。作用于ACR-16受体的激动剂有可能规避对不作用于ACR-16受体的驱虫药（如左旋咪唑）的耐药性。
