New 1,2,3,4-tetrahydroisoquinoline Derivatives As Modulators of Proteolytic Cleavage of Amyloid Precursor Proteins

A type of new 1,2,3,4-tetrahydroisoquinoline derivatives was synthesized via concise procedure from commercially available tetrahydroisoquinoline. These derivatives were delicately designed to possess propargyl-related pharmacophores simulated with a monoamine oxidase inhibitor rasagiline. We investigated the effect of these synthetic tetrahydroisoquinoline derivatives on the regulation of proteolytic processing of amyloid precursor protein (APP) by an ERK-dependent signaling pathway. Additionally, these compounds were also evaluated on the prevention of the proteolytic processing of C99 as gamma-secretase inhibitors by using a highly efficient cell-based reporter gene assay for gamma-secretase. The results suggested that certain compounds might be explored to possess both sAPPalpha-releasing stimulation and gamma-secretase inhibitory potency, which may reflect the synergetic potential of neuroprotective activities for the treatment of Alzheimer's disease as they possessed both ERK activation and inhibition of amyloidogenic Abeta release.