Discovery and synthesis of hydroxy-L-proline based blockers of the neutral amino acid transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2)

Abstract

AbstractThe conformationally restricted heterocycle hydroxy-L-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened a series of hydroxy-L-proline derivatives or ‘prolinols’ using electrophysiological and radio-labeled uptake assays on amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We identified a number of synthetic prolinols that act as selective high-affinity inhibitors of the SLC1 functional subfamily comprising the neutral amino acid transporters SLC1A4 and SLC1A5. The active and inactive prolinols were computationally docked into a threaded homology model and analyzed with respect to predicted molecular orientation and observed pharmacological activity. The series of hydroxy-L-proline derivatives identified here represents a new class of potential agents to pharmacologically modulate SLC1A4 and SLC1A5, amino acid exchangers that play important roles in a wide range of physiological and pathophysiological processes.