Synthesis of novel 1-phenyl-benzopyrrolizidin-3-one derivatives and evaluation of their cytoneuroprotective effects against NMDA-induced injury in PC12 cells

• Published in: Bioorganic & medicinal chemistry Vol. 59; p. 116675
• Main Authors: Yang, Lishou, Yang, Qian, Wang, Enhua, Yang, Juan, Li, Qiji, Cao, Jiafu, Wang, Li, Liao, Xiu, Yang, Yan, Yang, Xiaosheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2022
• Subjects: 1-Phenyl-benzopyrrolizidin-3-one; Animals; Calcium - metabolism; Excitotoxicity; N-methyl-ᴅ-aspartate; N-Methylaspartate - toxicity; Neuroprotective Agents - pharmacology; Neuroprotective effect; PC12 Cells; Rats; Receptors, N-Methyl-D-Aspartate; N-methyl-ᴅ-aspartate; Neuroprotective effect; 1-Phenyl-benzopyrrolizidin-3-one; Excitotoxicity; PC12 cells
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116675

[Display omitted] •Synthesis of 28 novel 1-phenyl-benzopyrrolizidin-3-one derivatives.•Compound 11 m has shown good neuroprotective effect on NMDA-induced injury in PC12 cells via Ca2+ antagonism.•Docking 11 m into the glycine binding site of NMDAR to explain protective potency. A range of novel 1-phenyl-benzopyrrolizidin-3-one derivatives were synthesized and evaluated for neuroprotective effects against N-methyl-ᴅ-aspartate (NMDA)-induced injury in PC12 cells. Interestingly, derivatives that 1-phenyl moiety bearing electron-donating group, especially benzyloxy, and the trans-forms exhibited better protective activity against NMDA-induced neurotoxicity. Compound 11 m demonstrated the best neuroprotective potency and shown a dose-dependent prevention. The increased intracellular calcium (Ca2+) influx caused by NMDA in PC12 cells was reversed in the case of compound 11 m pretreatment at 15 μM. These results suggested that the synthesized 1-phenyl-benzopyrrolizidin-3-one derivatives exerted neuroprotective effect on NMDA-induced excitotoxicity in PC12 cells associated with inhibition of Ca2+ overload and can be further optimized for the development of neuroprotective agents.