title: (S)-5-ethynyl-anabasine, a novel compound, is a more potent agonist than other nicotine alkaloids on the nematode Asu-ACR-16 receptor.
abstract: 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 (EC506.21 ± 0.56 μM, Imax82.39 ± 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 (EC50s) of the agonists. Here, we describe the synthesis of a novel agonist, (S)-5-ethynyl-anabasine, and show that it is more potent (EC500.14 ± 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.
authors.affiliation: Department of Chemistry, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
authors.forename: Fudan
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Physics and Astronomy, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Chou
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Robertson
authors.affiliation: Department of Physics and Astronomy, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Yu
authors.affiliation: Department of Chemistry, College of Liberal Arts and Sciences, Iowa State University, Ames, IA, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: VanVeller
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA. Electronic address: rjmartin@iastate.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017165:Ascaris suum / Q000235:genetics / Q000378:metabolism*; D055808:Drug Discovery; D007978:Levamisole / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009865:Oocytes; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014981:Xenopus / Q000235:genetics
chemical_list: C000624192:5-ethynylanabasine; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D007978:Levamisole; D000691:Anabasine
keywords: Agonist-binding site; Anthelmintic; Ascaris suum; Asu-ACR-16; Nicotine alkaloids; Xenopus expression