Chen_2019_Mol.Divers_23_709

A series of 8- and 11-substituted hybrids of oxoisoaporphine-tetrahydroisoquinoline have been designed and synthesized. The new derivatives strongly suppressed NO and iNOS production and modulated the production of cytokines by decreasing TNF-alpha and IL-1beta formation in lipopolysaccharide-activated BV-2 microglia and RAW 264.7 macrophages. Meanwhile, incubation of these derivatives with SH-SY5Y cells that were transfected with human APP containing the Swedish mutations significantly decreased the secretion of Abeta42. Moreover, these hybrids could strongly inhibit the activity of acetylcholinesterase and butyrylcholinesterase. Further investigations in vivo indicated that the 8-substituted hybrid 3b significantly delayed paralysis caused by Abeta1-42 toxicity in GMC101. In sum, these new hybrids could target multiple pathogenetic factors in Alzheimer's disease and merit further investigation.