Cognitive Improvements in a Mouse Model with Substituted 1,2,3-Triazole Agonists for Nicotinic Acetylcholine Receptors
文摘
The 伪7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent 伪7-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 伪7 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 渭mol/kg for IND8 and 10 渭mol/kg for QND8), ORT (10 渭mol/kg), and water maze test (25 渭mol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 渭mol/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 伪7-nAChRs as evidenced by its complete abolition after pretreatment with a selective 伪7-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.