Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity

• Published in: Molecular neurobiology Vol. 54; no. 9; pp. 6697 - 6722
• Main Authors: Machhi, Jatin, Prajapati, Navnit, Tripathi, Ashutosh, Parikh, Zalak S., Kanhed, Ashish M., Patel, Kirti, Pillai, Prakash P., Giridhar, Rajani, Yadav, Mange Ram
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2017; Springer Nature B.V
• Subjects: Animal models; Animals; Apoptosis; Benzazepines - administration & dosage; Benzazepines - chemical synthesis; Benzazepines - metabolism; Binding sites; Biology; Biomedical and Life Sciences; Biomedicine; Calcium influx; Cell Biology; Cell culture; Cell death; Cell Line, Tumor; Cells, Cultured; Chemical synthesis; Drug Delivery Systems - methods; Drug Evaluation, Preclinical - methods; Excitatory Amino Acid Antagonists - administration & dosage; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - metabolism; Excitotoxicity; Free radicals; Glutamate receptors; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Glycine; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Hippocampus; Humans; MAP kinase; N-Methyl-D-aspartic acid receptors; Neurobiology; Neurodegeneration; Neurology; Neuroprotection; Neurosciences; Neurotransmission; Phosphorylation; Rats; Receptors, Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Tau protein; Toxicity; NMDAR; Alzheimer’s disease; Excitotoxicity; Benzazepine derivatives
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-016-0184-9

Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3 H -benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells. In order to assess the multi-target-directed potential of the synthesised compounds, Aβ 1–42 aggregation inhibitory activity of the most potent benzazepines was evaluated using thioflavin T (ThT) and Congo red (CR) binding assays as Aβ also imparts toxicity, at least in part, through NMDAR overactivation. Furthermore, neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic activities of the two potential test compounds ( 7 and 14 ) were evaluated using primary rat hippocampal neuronal culture against Aβ 1–42 -induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aβ 1–42 -induced toxicity. All of the synthesised benzazepines have shown significant neuroprotection against NMDA-induced excitotoxicity. The most potent compound ( 14 ) showed relatively higher affinity for the glycine binding site as compared with the glutamate binding site of NMDAR in the molecular docking studies. 7 and 14 have been shown experimentally to abrogate Aβ 1–42 aggregation efficiently. Additionally, 7 and 14 showed significant neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic properties in different in vitro and in vivo experimental models. Finally, 7 and 14 attenuated Aβ 1–42 -induced tau phosphorylation by abrogating activation of tau kinases, i.e. MAPK and GSK-3β. Thus, the results revealed multi-target-directed potential of some of the synthesised novel benzazepines against excitotoxicity.