119754-20-0Relevant academic research and scientific papers
Selectivity Optimization of Substituted 1,2,3-Triazoles as α7 Nicotinic Acetylcholine Receptor Agonists
Arunrungvichian, Kuntarat,Fokin, Valery V.,Vajragupta, Opa,Taylor, Palmer
, p. 1317 - 1330 (2015)
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 5HT3A receptors, 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 5HT3A receptors. 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).
SELECTIVE ALPHA-7 NICOTINIC RECEPTOR AGONISTS AND METHODS FOR MAKING AND USING THEM
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Paragraph 0211; 0212, (2018/09/16)
In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (α7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (α7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole (“IND1”), 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”). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.
Synthesis of Some Substituted Dimethyl and Diethyl 4-(Phenylethynyl)-2,6-pyridinedicarboxylates
Takalo, Harri,Kankare, Jouko,Haenninen, Elina
, p. 448 - 454 (2007/10/02)
Substituted dimethyl and diethyl 4-(phenylethynyl)-2,6-pyridinedicarboxylates were prepared by coupling reactions between dialkyl 4-halo-2,6-pyridinedicarboxylates and terminal arylacetylenes in the presence of an organopalladium catalyst and copper(I) iodide in a suitable solvent system.The terminal acetylenes needed in this work were synthesized from the corresponding aryl halides using either (trimethylsilyl)acetylene or 2-methyl-3-butyn-2-ol followed by deprotection of the triple bond, depending on the nature of the compound in question.
