PuSH - Publikationsserver des Helmholtz Zentrums München: Development of an (<em>S</em>)-1-{2-[Tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(<em>S</em>)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4.

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Pabel, J.* ; Faust, M.* ; Prehn, C. ; Wörlein, B.* ; Allmendinger, L.* ; Höfner, G.* ; Wanner, K.T.*

Development of an (S)-1-{2-[Tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4.

ChemMedChem 7, 1245-1255 (2012)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT14 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4-methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl moiety (DDPM-1457) were found to exhibit pIC50 values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC50=5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114.

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