Development of imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors

A new series of potential GABA uptake inhibitors starting from of 1H-imidazol-4-ylacetic acid with the carboxylic acid side chain originating from different positions and varying in length have been synthesized and tested for the inhibitory potency at the four GABA uptake transporters mGAT1–4 stably expressed in HEK cells. Further two bicyclic compounds with a rigidified carboxylic acid side chain were included in this study. The results of the biological tests indicated that most ω-imidazole alkanoic and alkenoic acid derivatives exhibit the highest potencies as GABA uptake inhibitors at mGAT3.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights►Imidazolyl alkanoic acids have been synthesized and evaluated for their potency as GABA uptake inhibitors. ► The structure of 1H-imidazol-4-ylacetic acid has been varied regarding length and position of the carboxylic acid side chain. ► Also two bicyclic analogs of imidazolyl alkanoic acid were evaluated for inhibitory potencies at mGAT1-4. ► Higher potencies of imidazolyl alkanoic acids are observed for mGAT3.