On the other hand, the configuration of the S-isomer imparts a highly restrictive conformation on the enzyme–ligand complex, which prevents the molecule from entering the catalytic site, precluding it from acting as a mechanism-based inhibitor. Interestingly, the neuroprotective activity associated with these compounds has now been shown to be associated with the ability of propargylamine36,37 to protect mitochondrial viability by activation of Bcl-2

and protein kinase C (PKC)-α and -ε and by down-regulating proapoptotic FAS and Bax, and PKCδ and -γ.33 Inhibitors,research,lifescience,medical Additionally, these drugs induce the release of the soluble neuroprotective-neurotrophic form of the amyloid precursor protein α (sAPPα) through a PCK-MAP-mediated activation of α-secretase.27 The

identification of the propargylamine moiety Inhibitors,research,lifescience,medical as a key element that confers neuroprotective activity and, in cases such as rasagiline and selegiline, also MAO-inhibitory activity, led to the development of acetylcholinesterase (AChE) inhibitors such as ladostigil (TV3326, now in phase II clinical studies), another anti-Alzheimer’s disease/anti-Parkinson’s/ antidepressant drug. 27,33,38,39 Ladostigil (chemical structure Figure 4) is a dual acetylcholine-butyrylcholine-esterase and brain-selective MAO-A/B Inhibitors,research,lifescience,medical inhibitor in vivo, designed by combining the carbamate cholinesterase inhibitory moiety found in the rivastigmine molecule, with the pharmacophore of rasagiline and TVP1022, both of which possess the propargylamine Inhibitors,research,lifescience,medical moiety. Ladostigil

has been shown to have antidepressant activity, due to its ability to inhibit MAO-A in the raphe nucleus, striatum, hippocampus, and hypothalamus, and to raise brain levels of DA, norepinephrine, and serotonin.39 Its ability also to inhibit MAO-B attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity Inhibitors,research,lifescience,medical in mice, a rodent model of Parkinsonism.40 Although a poor MAO-B inhibitor, the S-isomer of ladostigil, TV3279, has shown similar neuroprotective activity to rasagiline and ladostigil in vitro and in laboratory animals,27 with molecular mechanisms apparently identical to that of rasagiline. Figure 4 Design of the multimodal anti-Alzheimer drug ladostigil, where the carbamate cholinesterase inhibitor moiety is introduced into rasagiline in order also to posses the Non-specific serine/threonine protein kinase monoamine oxidase inhibitory and neuroprotective activity of the latter drug. IRON CHELATORS WITH RADICAL SCAVENGING AND BRAIN-SELECTIVE MONOAMINE OXIDASE-INHIBITORY ACTIVITY Degenerating nigrostriatal DA neurons are the main pathological feature in the SNpc of PD sufferers. In addition, many PD patients also experience dementia and depression that likely result from sporadic neurodegeneration in cholinergic, noradrenergic, and serotonergic pathways.