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

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Abstract

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-3H-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, Aβ1–42 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 Aβ1–42-induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aβ1–42-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 Aβ1–42 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 Aβ1–42-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.

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Acknowledgements

The authors acknowledge the funding given by University Grants Commission, New Delhi, India, to Prof. Rajani Giridhar in the form of Major Research Project (F. no. 41-716/2012-SR). Authors also acknowledge Dr. Vikram Sarabhai Research Center, The Maharaja Sayajirao University of Baroda, Vadodara, India for providing analytical facilities.

Author Contributions

JM designed the study; MRY, RG and NP designed, synthesised and characterised the compounds; NP performed the synthesis of compounds; JM performed all the in vitro and in vivo biological experiments and collected data; JM and NP wrote the manuscript; AMK performed the molecular docking studies; AT, ZSP and JM performed in vitro experiments on primary rat hippocampal neuronal culture and Western blot analysis under the supervision of PPP; MRY, RG, KP and PPP conceived, designed and approved the final version of the manuscript. All authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

    Jatin Machhi, Navnit Prajapati, Ashish M. Kanhed, Kirti Patel, Rajani Giridhar & Mange Ram Yadav

  2. Division of Neurobiology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India

    Ashutosh Tripathi, Zalak S. Parikh & Prakash P. Pillai

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  1. Jatin Machhi
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  2. Navnit Prajapati
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Correspondence to Mange Ram Yadav.

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Machhi, J., Prajapati, N., Tripathi, A. et al. Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity. Mol Neurobiol 54, 6697–6722 (2017). https://doi.org/10.1007/s12035-016-0184-9

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  • DOI: https://doi.org/10.1007/s12035-016-0184-9

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