title: New 1,2,3,4-tetrahydroisoquinoline derivatives as modulators of proteolytic cleavage of amyloid precursor proteins.
abstract: 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.
authors.affiliation: School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Section 6, Taipei 114, Taiwan. hmk@ndmctsgh.edu.tw
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
authors.forename: Jung-Fang
authors.initials: JF
authors.lastname: Chen
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.forename: Ying-Tsen
authors.initials: YT
authors.lastname: Tung
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Lin
authors.forename: Kang-Po
authors.initials: KP
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D018696:Neuroprotective Agents; D010447:Peptide Hydrolases / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases