Pharmacological Diversity of nAChRs in Clade III Nematodes: Levamisole receptors

进化枝 III 线虫中 nAChR 的药理学多样性：左旋咪唑受体

• 批准号: 8786864
• 负责人: Richard John Martin
• 金额: $ 35.95万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786864
• 关键词: Adult; Affect; Agonist; Animals; Anthelmintics; Ascariasis; Ascaris; Ascaris lumbricoides; Ascaris suum; Biological Assay; Brugia; Brugia malayi; Caenorhabditis elegans; China; Cloning; Complex; Country; Development; Disease; Dose; Drosophila acetylcholine receptor alpha-subunit; Drug Combinations; Drug Controls; Drug effect disorder; Elephantiasis; Figs - dietary; Filarial Elephantiases; Future; Health; Human; Intestines; Investigation; Ion Channel; Knowledge; Lactones; Larva; Lead; Levamisole; Methods; Molecular; Muscle; Muscle Contraction; Nematoda; Nicotinic Receptors; Outcome; Parasites; Parasitic Diseases; Parasitic nematode; Pharmaceutical Preparations; Pharmacology; Preparation; Prevention; Property; Refractory; Research; Research Personnel; Resistance; Resistance development; Site; Surgical Flaps; System; Testing; Therapeutic; Therapeutic Effect; Toxin; Vaccines; Variant; Xenopus oocyte; avermectin; channel blockers; chemotherapy; cholinergic; drug development; filaria; improved; innovation; levamisole resistance; neglected tropical diseases; novel; patch clamp; receptor; response; stoichiometry; synergism; transmission process; voltage clamp; voltage/patch clamp

DESCRIPTION (provided by applicant): 1. The Neglected Tropical Diseases include ascariasis and lymphatic filariasis. These diseases are caused by parasitic nematodes that are grouped in Clade III because of their molecular similarities. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries; it is caused by filaria nematodes like Brugia malayi. Control of these nematode parasites (adults or larvae) relies on a limited number of anthelmintic drugs. There are concerns that mass chemotherapy will lead to the development of resistance. There is a significant and urgent need for research that will allow better use of existing drugs, including combinations, to preserve their value, and to develop new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, like tribendimidine and derquantel (now synergized with abamectin), have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has 'resistance busting' actions against worms that are resistant to other cholinergic anthelmintics. The pharmacology of nematode nicotinic receptors (nAChRs) is more complex than has been appreciated. The muscle nAChRs are divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III muscle receptors (levamisole receptors) are modulated by receptor subunit composition. The therapeutic importance of subtypes and modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patch- clamp, cloning & Xenopus oocyte expression and pharmacological agents, to characterize actions of cholinergic anthelmintics and the subtypes of their receptors. Aim #1 will characterize the mode of action and subtype selectivity of tribendimidine in A. suum. It will test the hypothesis that tribendimidine is not selective for the L-subtype of nAChR but another type in A. suum and determine if its action as an open-channel blocker limits efficacy. Aim #2 will examine the effects of subunit arrangements and stoichiometry on pharmacology of Ascaris nAChRs. It will express four specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that different subunit compositions reproduce the pharmacological diversity of native muscle receptors (levamisole receptors). Aim #3 will characterize nAChR responses and receptors in B. malayi, to test the hypothesis that the subtypes are functionally similar to the Clade III nematode, A. suum. 4. The proposal is innovative, exploring unknown drug effects and effects of subunit arrangements on the pharmacological properties of Clade III nAChRs. We also extend, to the Brugia malayi parasite preparation, the methods that this group of investigators has developed. 5. The overall impact will be a powerful influence on: expansion & informed use of tribendimidine, a potential single-dose MDA; the expansion and informed use of the pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes; use of a novel B. malayi preparation for studying ion-channel targets for future drug development; development or informed use of combinations (e.g. derquantel with avermectins; or combinations of subtype selective cholinergic anthelmintics).

描述（由申请人提供）：被忽视的热带病包括蛔虫病和淋巴丝虫病。这些疾病是由寄生线虫引起的，由于它们的分子相似性，它们被归为III类。蛔虫病是由大肠蛔虫（蛔虫）引起的。全世界有14亿人患有此病。淋巴丝虫病（象皮病）威胁着83个国家的10亿多人；它是由丝状线虫引起的，比如马来西亚布鲁吉亚线虫。控制这些线虫寄生虫（成虫或幼虫）依赖于数量有限的驱虫药。有人担心大规模化疗会导致耐药性的产生。迫切需要进行重大研究，以便更好地利用现有药物，包括联合用药，以保持其价值，并开发新药。2. 最近，一些新的线虫选择性胆碱能驱虫药，如三苯二胺和德quantel（现已与阿维菌素协同）被引入，增加了胆碱能驱虫药的意义。三苯二咪定有潜力作为单剂量大规模药物管理。Derquantel对那些对其他胆碱能驱虫药有抗药性的蠕虫具有“破药”作用。线虫烟碱受体（nAChRs）的药理学比人们所认识的要复杂得多。肌肉nachr在猪蛔虫中分为N-、L-和b -亚型。Clade III肌肉受体（左旋咪唑受体）的药理作用受受体亚基组成的调节。寄生线虫的亚型和调节的治疗重要性需要进一步研究。我们有三个目标。3. 我们的方法将使用肌肉收缩试验、电流钳、电压钳、膜片钳、克隆和爪蟾卵母细胞表达以及药理学试剂来表征胆碱能驱虫药的作用及其受体亚型。目的1将描述三苯二胺在黄芪中的作用方式和亚型选择性。它将检验三苯二胺对nAChR的l亚型没有选择性，而对A. suum中的另一种类型有选择性的假设，并确定其作为开放通道阻滞剂的作用是否会限制疗效。目的2将研究亚基排列和化学计量对蛔虫nachr药理学的影响。它将以不同的组合表达四种特定的烟草受体亚基，以验证不同亚基组合再现天然肌肉受体（左旋咪唑受体）的药理学多样性的假设。Aim #3将表征马来芽孢杆菌的nAChR反应和受体，以验证该亚型在功能上与III枝线虫相似的假设。4. 该提案是创新的，探索未知的药物作用和亚基排列对Clade III nAChRs药理学性质的影响。我们还将这组研究人员开发的方法扩展到马来布鲁吉亚寄生虫的制备。5. 总体影响将对以下方面产生强有力的影响：三苯二胺（一种潜在的单剂量丙二胺）的扩大和知情使用；III级线虫中烟碱驱虫靶点药理多样性的扩展和知情利用；利用一种新的马来芽孢杆菌制剂研究离子通道靶点，为未来的药物开发做准备；开发或明智地使用组合（例如，德quantel与阿维菌素；或亚型选择性胆碱能驱虫药的组合）。