Amyloid beta (AO) oligomers and oxidative stress, typical of Alzheimer's disease, are highly neurotoxic. Previously we identified ATP-gamma-S as a most promising antioxidant and neuroprotectant To further improve both potency and metabolic stability of ATP-gamma-S, we designed a related analogue, ATP-gamma-S-(alpha,beta-CH2). We found that ATP-gamma-S-(alpha,beta-CH2) effectively inhibited ROS formation in PC12 cells subjected to Fe(II)-oxidation, slightly better than ATP-gamma-S (IC50 0.18 and 0.20 mu M, respectively). Moreover, ATP-gamma-S-(alpha,beta-CH2) rescued primary neurons from A beta(42) toxicity, 4-fold more potently than ATP-gamma-S, (IC50 0.2 and 0.8 mu M, respectively). In addition, the metabolic stability of ATP-gamma-S-(alpha,beta-CH2) in PC12 cells during 4 h of incubation, was up to 20% greater than that of ATP-gamma-S and ATP. Previously, we found that ATP-gamma-S-(alpha,beta-CH2) resisted hydrolysis by ecto-nucleotidases such as, NPPs and TNAP, and was found to be similar to 7-fold more potent agonist than ATP at P2Y11 receptor. Therefore, we propose ATP-gamma-S-(alpha,beta-CH2) as a promising agent for rescue of neurons from insults typical of Alzheimer's disease. (C) 2015 Elsevier Inc. All rights reserved.