Methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor and plays an important role in neuronal degradation of Alzheimer ' s disease (AD). According to molecular modeling docking studies, we have designed the compound Arg-Glu-ArgMet-Ser-(3,5)-dimethyladamantan-1-amine (RERMS-MEM), consisting of an A ss PP 5-mer peptide (RERMS) and memantine (MEM). -is compound could dock into the active sites of N-methyl-D-aspartate receptor type 2B (NMDAR2B) with a -64.14 kcal/mol CDOCKER interaction energy. The stability of RERMS-MEM was evaluated through a 50 ns molecular dynamics simulation. The results revealed that the docked ligand-receptor complex was stable. Furthermore, surface plasmon resonance (SPR) revealed that the RERMS-MEM binding affnity to the NMDAR2B fragment exhibited over 15-fold enhancement compared to MEM. The SH-SY5Y cell assays showed that RERMS-MEM or RERMS at concentrations of 0.1, 1, 10, or 50 mu Mcould enhance the metabolic rate, and MEM showed no diAerence compared to the control and indicated cytotoxic eAects at 50 mu M. RERMS-MEM at concentrations of 0.01, 0.1, 1, 10, or 50 mu Mincreased the number of viable cells and reduced the release of lactate dehydrogenase (LDH). RERMS at concentrations of 10 or 50 mu M was similar to RERMS-MEM for increasing viable cells, and MEM showed no diAerence compared to the control and decreased the number of viable cells at 50 mu M. RERMS-MEM or RERMS at concentrations of 10 or 50 mu Mcould antagonize A. 25-35-induced cytotoxicity, and MEM at 50 mu Mstrengthened the cytotoxicity eAects. The results revealed that RERMS-MEM showed a strong NMDAR-blocking activity as a potential NMDAR antagonist, enhancing the neurotrophic eAect and cellular growth in SH-SY5Y cells.