title: Cognitive improvements in a mouse model with substituted 1,2,3-triazole agonists for nicotinic acetylcholine receptors.
abstract: The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization.
authors.affiliation: †Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand.
authors.forename: Kuntarat
authors.initials: K
authors.lastname: Arunrungvichian
authors.affiliation: ‡Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Science, KhonKaen University, 123 Muang, KhonKaen 40002, Thailand.
authors.forename: Chantana
authors.initials: C
authors.lastname: Boonyarat
authors.affiliation: §Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.affiliation: ∥Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0650, United States.
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.affiliation: †Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand.
authors.forename: Opa
authors.initials: O
authors.lastname: Vajragupta
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D018697:Nootropic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012601:Scopolamine; D013619:Tacrine / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D018697:Nootropic Agents; C498513:PNU-282987; D064569:alpha7 Nicotinic Acetylcholine Receptor; D013619:Tacrine; D012601:Scopolamine
keywords: behavioral memory loss; cognitive improvement; modified Y-maze; object recognition test (ORT); water maze; α7-nAChR agonist