title: Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity.
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, Aβ1-42aggregation 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 Aβ1-42aggregation 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.
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Jatin
authors.initials: J
authors.lastname: Machhi
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Navnit
authors.initials: N
authors.lastname: Prajapati
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Zalak S
authors.initials: ZS
authors.lastname: Parikh
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kanhed
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Kirti
authors.initials: K
authors.lastname: Patel
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Prakash P
authors.initials: PP
authors.lastname: Pillai
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.affiliation: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India. mryadav11@yahoo.co.in.
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001552:Benzazepines; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Alzheimer’s disease; Benzazepine derivatives; Excitotoxicity; NMDAR