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Weinreb O.,Rappaport Family Research Institute
Journal of neural transmission (Vienna, Austria : 1996) | Year: 2011

It is for these authors a great privilege to dedicate this review article to Moussa Youdim, who is one of the most imperative pharmacologists and pioneer investigators in the search and development of novel therapeutics for neurodegenerative diseases. 40 years ago, Moussa Youdim has started studying brain iron, catecholamine receptor and monoamine oxidase (MAO)-A and -B functions. Although Moussa Youdim succeeded in exploring the novel anti-Parkinsonian, selective MAO-B inhibitor drug, rasagiline (Azilect, Teva Pharmaceutical Co.), he did not stop searching for superior therapeutic approaches for neurodegenerative disorders. To date, Moussa Youdim and his research group are designing and synthesizing pluripotential drug candidates possessing diverse pharmacological properties that can act on multiple targets and pathological features ascribed to Parkinson's disease, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. One such example is the multimodal non-toxic, brain-permeable iron-chelating compound, M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), which amalgamates the propargyl moiety of rasagiline with the backbone of the potent iron chelator, VK28. This review discusses the multiple effects of several leading compounds of this series, concerning their neuroprotective/neurorestorative molecular mechanisms in vivo and in vitro, with a special focus on the pathological features ascribed to AD, including antioxidant and iron chelating activities, regulation of amyloid precursor protein and amyloid β peptide expression processing, activation of pro-survival signaling pathways and regulation of cell cycle and neurite outgrowth.

Wang L.,Okayama University | Esteban G.,Autonomous University of Barcelona | Ojima M.,Okayama University | Bautista-Aguilera O.M.,CSIC - Institute of Polymer Science and Technology | And 12 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl) methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice. © 2014 Elsevier Masson SAS. All rights reserved.

Weinreb O.,Rappaport Family Research Institute | Amit T.,Rappaport Family Research Institute | Bar-Am O.,Rappaport Family Research Institute | Youdim M.B.H.,Rappaport Family Research Institute | Youdim M.B.H.,Yonsei University
Current Drug Targets | Year: 2012

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholine-esterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and up-regulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer's and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug. © 2012 Bentham Science Publishers.

Weinreb O.,Rappaport Family Research Institute | Bar-Am O.,Rappaport Family Research Institute | Prosolovich K.,Rappaport Family Research Institute | Amit T.,Rappaport Family Research Institute | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2011

The anti-Parkinsonian, monoamine oxidase-B inhibitor drug, rasagiline (Azilect ®), is primarily metabolized by hepatic cytochrome P450 isoenzyme 1A2-mediated N-dealkylation to form its major metabolite, 1-(R)-aminoindan. The present study was undertaken to further investigate, for the first time, the possible neuroprotective effect of 1-(R)-aminoindan in two rat models of Parkinson's disease, the 6-hydroxydopamine-and lactacystin (a proteasomal inhibitor)-induced nigrostriatal degeneration. 1-(R)-aminoindan reversed behavioral asymmetry and restored striatal catecholamine levels in these two rat models and significantly protected neurons from hydrogen peroxide-induced oxidative stress. These observations indicate that 1-(R)-aminoindan may contribute to the overall neuroprotective activity of its parental compound, rasagiline. © 2011, Mary Ann Liebert, Inc.

Bar-Am O.,Rappaport Family Research Institute | Weinreb O.,Rappaport Family Research Institute | Amit T.,Rappaport Family Research Institute | Youdim M.B.H.,Rappaport Family Research Institute
Journal of Neurochemistry | Year: 2010

The anti-parkinsonian drug, rasagiline [N-propargyl-1-(R)-aminoindan; Azilect®], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B) inhibition and possesses neuroprotective and neurorestorative activities. A prospective clinical trial has shown that rasagiline confers significant symptomatic improvement and demonstrated alterations in Parkinson's disease progression. Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, 1-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound. Recent studies indicated the potential neuroprotective effect of 1-(R)-aminoindan, suggesting that it may contribute to the overall neuroprotective and antiapoptotic effects of its parent compound, rasagiline. This review article briefly highlights the molecular mechanisms underlying the neuroprotective properties of the active metabolite of rasagiline, 1-(R)-aminoindan, supporting the valuable potential of rasagiline for disease modification. © 2010 International Society for Neurochemistry.

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