NA-014

NA-014 is a brain-penetrant piperazinyl-acetamide that functions as a highly selective positive allosteric modulator (PAM) of the excitatory amino acid transporter 2 (EAAT2), with no activity on EAAT1 and EAAT3. NA-014 effectively enhances EAAT2-mediated glutamate uptake, demonstrating an EC50 of 3.5 nM and an efficacy of 167.3% in EAAT1−3 transfected COS-7 cells, and an EC50 of 13.4 nM with 189.4% efficacy in glial cultures. NA-014 does not exhibit off-target effects on a broad panel of related receptors, including the hERG channel, displays good metabolic stability, possesses moderate water solubility, and shows favorable pharmacokinetic properties. Additionally, both enantiomers of NA-014 are active, binding at the allosteric site of human EAAT2 and demonstrating equivalent activity in functional assays designed to assess stimulation of EAAT2.