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Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands

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dc.contributor.author Joubert, Jacques
dc.contributor.author Malan, Sarel Francois
dc.contributor.author Van Dyk, Sandra
dc.contributor.author Green, I. van R.
dc.date.accessioned 2012-10-04T07:10:24Z
dc.date.available 2012-10-04T07:10:24Z
dc.date.issued 2011
dc.identifier.citation Joubert, J. et al. 2011. Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands. European journal of medicinal chemistry, 46(10):5010-5020. [http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/] en_US
dc.identifier.issn 0223-5234
dc.identifier.issn 1768-3254 (Online)
dc.identifier.uri http://hdl.handle.net/10394/7438
dc.description Published under the auspices of the French Société de Chimie Thérapeutique (SCT) en_US
dc.description.abstract A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-D-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibitionwas observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8e11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration. en_US
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.subject Polycyclic en_US
dc.subject amantadine en_US
dc.subject NMDAR en_US
dc.subject calcium channels en_US
dc.subject fluorescent ligands en_US
dc.title Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands en_US
dc.type Article en_US


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