2016
DOI: 10.1021/acs.jnatprod.6b00479
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Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

Abstract: A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC values similar to those of… Show more

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Cited by 8 publications
(31 citation statements)
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“…Experimental procedures for both functional assays are included in the Supporting Information. As observed for other series of strychnine analogues, , the IC 50 values obtained for the ligands in the patch-clamp recordings were generally lower than those from the FMP assay, but the two data sets reflect similar SAR, and there was an overall good correlation between the antagonist potencies exhibited by the compounds at α1 GlyR in the two assays (Figure S1, Supporting Information). As the residues essential for strychnine binding are largely conserved among the α and β subunits of GlyRs and as strychnine is an equipotent antagonist of homomeric and heteromeric GlyRs, it was not surprising that none of the analogues displayed selectivity toward one of the two subtypes in the two functional assays.…”
Section: Resultssupporting
confidence: 57%
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“…Experimental procedures for both functional assays are included in the Supporting Information. As observed for other series of strychnine analogues, , the IC 50 values obtained for the ligands in the patch-clamp recordings were generally lower than those from the FMP assay, but the two data sets reflect similar SAR, and there was an overall good correlation between the antagonist potencies exhibited by the compounds at α1 GlyR in the two assays (Figure S1, Supporting Information). As the residues essential for strychnine binding are largely conserved among the α and β subunits of GlyRs and as strychnine is an equipotent antagonist of homomeric and heteromeric GlyRs, it was not surprising that none of the analogues displayed selectivity toward one of the two subtypes in the two functional assays.…”
Section: Resultssupporting
confidence: 57%
“…On the contrary, in bivalent ligands linked through C-2 of strychnine, the spacer is expected to be projecting toward the top of the receptor, making simultaneous occupation of adjacent strychnine binding sites possible. Moreover, (strychnine-2-yl)­propionamide has been reported to display only 3–5-fold lower antagonistic potency at homomeric α1 GlyRs than strychnine . Consequently, the C-2 amide linker was chosen to attach the spacer to the strychnine pharmacophores in order to allow bridging across the central pore of homomeric α1 GlyRs.…”
Section: Resultsmentioning
confidence: 99%
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