Hybrids of oxoisoaporphine-tetrahydroisoquinoline: novel multi-target inhibitors of inflammation and amyloid-β aggregation in Alzheimer's disease.

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-α and IL-1β 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 Aβ42 . 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 Aβ1-42 toxicity in GMC101. In sum, these new hybrids could target multiple pathogenetic factors in Alzheimer's disease and merit further investigation.