Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation.
The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders. Both multifunctional propargylamine-derivatives were found to possess neuroprotective and anti-apoptotic properties. An additional and new neuroprotective effect, shared by the propargylamine-derivative compounds, is related to their ability to regulate the processing of amyloid-beta protein precursor (AbetaPP) by the non-amyloidogenic alpha-secretase pathway. This effect was shown to involve activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathway. This review will summarize and discuss current research, focused on the effect of propargylamine-related derivatives on the proteolytic processing of AbetaPP and signal transduction mechanisms.
Bar-Am
Orit
O
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
Amit
Tamar
T
Weinreb
Orly
O
Youdim
Moussa B H
MB
Mandel
Silvia
S
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases