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.