title: High-Throughput Screening for Positive Allosteric Modulators Identified Potential Therapeutics against Acetylcholinesterase Inhibition.
abstract: The current standard of care for treatment of organophosphate (OP) poisoning includes pretreatment with the weak reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide. Because this drug is an AChE inhibitor, similar side effects exist as with OP poisoning. In an attempt to provide a therapeutic capable of mitigating AChE inhibition without such side effects, high-throughput screening was performed to identify a compound capable of increasing the catalytic activity of AChE. Herein, two such novel positive allosteric modulators (PAMs) of AChE are presented. These PAMs increase AChE activity threefold, but they fail to upshift the apparent IC50 of a variety of OPs. Further development and optimization of these compounds may lead to pre- and/or postexposure therapeutics with broad-spectrum efficacy against pesticide and nerve agent poisoning. In addition, they could be used to complement the current therapeutic standard of care to increase the activity of uninhibited AChE, potentially increasing the efficacy of current therapeutics in addition to altering the therapeutic window.
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA richard.chapleau.1@us.af.mil.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Chapleau
authors.affiliation: College of Pharmacy, Ohio State University, Columbus, OH, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: McElroy
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ruark
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Fleming
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Ghering
authors.affiliation: Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Schlager
authors.affiliation: Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Poeppelman
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Wright Patterson AFB, OH, USA Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory (711 HPW/RHDJ), Wright Patterson AFB, OH, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Gearhart
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000494:Allosteric Regulation; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D020536:Enzyme Activators / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D062025:Organophosphate Poisoning / Q000188:drug therapy*
chemical_list: D002800:Cholinesterase Inhibitors; D020536:Enzyme Activators; D000110:Acetylcholinesterase
keywords: acetylcholinesterase; medical countermeasure; nerve agent pretreatment; organophosphate poisoning; positive allosteric modulator