Kuntarat ArunrungvichianValery V. FokinOpa VajraguptaPalmer TaylorMahidol UniversityUniversity of California, San DiegoScripps Research Institute2018-11-232018-11-232015-08-19ACS Chemical Neuroscience. Vol.6, No.8 (2015), 1317-1330194871932-s2.0-84939806224https://repository.li.mahidol.ac.th/handle/20.500.14594/35396© 2015 American Chemical Society. Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, α7-nAChRs, α4β2-nAChRs, and 5HT3Areceptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with Kds at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the α7-nAChRs over α4β2-nAChRs and 5HT3Areceptors. Lead compounds in the three series have EC50s between 28 and 260 nM. Based on the EC50, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059).Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1021/acschemneuro.5b00058