Design, Synthesis, and Neurotrophic Effect of Arg-Glu-Arg-Met-Ser-(3,5)-Dimethyladamantan-1-Amine In Vitro Evaluations as a Potential NMDAR Antagonist

Author:

Wang Xiaozhen1ORCID,Li Ze2ORCID,Zhang Xiaoyi3ORCID,Kang Meimei1ORCID,Lv Caizhen1ORCID,Zhang Xu1ORCID,Zhao Zhiwei1ORCID,Wu Yanchuan1ORCID,Song Penghui1ORCID,Wang Rong14ORCID

Affiliation:

1. Department of Central Laboratory, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Geriatric Medical Research Center, Beijing, China

2. Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China

3. School of Pharmaceutical Sciences, Capital Medical University, Beijing, China

4. Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China

Abstract

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-Arg-Met-Ser-(3,5)-dimethyladamantan-1-amine (RERMS-MEM), consisting of an AβPP 5-mer peptide (RERMS) and memantine (MEM). This 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 affinity 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 μM could enhance the metabolic rate, and MEM showed no difference compared to the control and indicated cytotoxic effects at 50 μM. RERMS-MEM at concentrations of 0.01, 0.1, 1, 10, or 50 μM increased the number of viable cells and reduced the release of lactate dehydrogenase (LDH). RERMS at concentrations of 10 or 50 μM was similar to RERMS-MEM for increasing viable cells, and MEM showed no difference compared to the control and decreased the number of viable cells at 50 μM. RERMS-MEM or RERMS at concentrations of 10 or 50 μM could antagonize Aβ25-35-induced cytotoxicity, and MEM at 50 μM strengthened the cytotoxicity effects. The results revealed that RERMS-MEM showed a strong NMDAR-blocking activity as a potential NMDAR antagonist, enhancing the neurotrophic effect and cellular growth in SH-SY5Y cells.

Funder

National Basic Research Program of China

Publisher

Hindawi Limited

Subject

General Chemistry

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