Novel Dual Inhibitors of AChE and MAO Derived from Hydroxy Aminoindan and Phenethylamine as Potential Treatment for Alzheimer's Disease.

Sterling, Jeffrey; Herzig, Yaacov; Goren, Tamar; Finkelstein, Nina; Lerner, David N.; Goldenberg, Willy; Miskolczi, I.; Molnár, Sándor; Rantal, F.; Tamás, Tivadar; Tóth, György; Zagyva, Adela; Zékány, A.; Finberg, J. P. M.; Lavian, Gila; Gross, Aviva; Friedman, Rachel S.; Razin, Michal; Huang, Wei; Krais, Boris; Chorev, Michael; Youdim, Moussa B. H.; Weinstock, Marta

doi:10.1021/jm030124x

Cited by 11 publications

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“…The results indicated that the N-PEG-TsDPEN ligand was favorable for particular steric substrates. The excellent ee values for these substrates, for example, 2,3-dihydro-1H-inden-1-ol or its derivatives, provide an alternative method for the preparation of key intermediates of several important drugs, including the neuroprotective and anti-AChE agents, Rasagiline [16] and Ladostigil [17] (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application in asymmetric transfer hydrogenation of ketones in neat water

Shan

Meng

et al. 2011

Journal of Organometallic Chemistry

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Section: Resultsmentioning

confidence: 99%

The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application in asymmetric transfer hydrogenation of ketones in neat water

Shan

Meng

et al. 2011

Journal of Organometallic Chemistry

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“…A series of analogs were synthesized with a carbamate cholinesterase inhibitory moiety in the aminoindan structure of rasagiline with the purpose of preserving its neuroprotective activity and also to inhibit acethylcholinesterase to increase cholinergic transmission, as a potential treatment for Alzheimer's disease and Lewy body disease (Weinstock et al 2000a;Sterling et al 2002;Youdim and Weinstock 2002b). Among these compounds, the R enantiomer, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], has many of the neuroprotective actions of rasagiline, such as prevention of the fall in the mitochondrial potential and cytotoxicity in human neuroblastoma SH-SY5Y and PC-12 cells in response to oxidative stress induced by peroxynitrite or glucose-oxygen deprivation (Wadia et al 1998;Weinstock et al 2000b;Maruyama et al 2003;Yogev-Falach et al 2006).…”

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confidence: 99%

Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro

Bar-Am

Amit

Youdim

2007

Journal of Neurochemistry

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The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 lmol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindaninduced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCe. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.

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“…In the present study, the terminal half life of enzyme activity was faster for MAO-A than for MAO-B in both the hippocampus and striatum. The biphasic nature of the recovery of activity of both MAO enzymes from the inhibition by TV3326 may be explained by the fact that TV3326, gives rise to a number MAO inhibitory metabolites (Sterling et al 2002;Youdim and Weinstock 2002). These are generated as a consequence of the dealkylation and hydrolysis of the carbamate moiety on the 6 position of the aminoindan structure.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of MPTP‐induced dopaminergic neurotoxicity by TV3326, a cholinesterase‐monoamine oxidase inhibitor

Sagi

Weinstock

Youdim

2003

Journal of Neurochemistry

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Abstract(R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.

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Novel Dual Inhibitors of AChE and MAO Derived from Hydroxy Aminoindan and Phenethylamine as Potential Treatment for Alzheimer's Disease.

Cited by 11 publications

References 0 publications

The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application in asymmetric transfer hydrogenation of ketones in neat water

The synthesis of a new nitrogen joined N-PEG-TsDPEN ligand and its application in asymmetric transfer hydrogenation of ketones in neat water

Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro

Attenuation of MPTP‐induced dopaminergic neurotoxicity by TV3326, a cholinesterase‐monoamine oxidase inhibitor

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