Executive Summary: Multimodal Drugs Under Development |
Introduction
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PD, AD, and ALS are progressive neurodegenerative diseases.
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Multiple molecular pathways are involved in the cell death process.
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Single targeted ligands may not modify the cell death process since the other pathways may still be contributing to cell death.
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Multifunctional ligands can be designed to target more than one drug target in PD, AD, and ALS.
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Rasagiline
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Rasagiline is a second-generation MAO-B inhibitor.
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It is used for the treatment of PD.
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It has also been shown to be neuroprotective and neurorestorative.
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It may be the first neuroprotective disease-modifying drug.
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Ladostigil-Monoamine Oxidase-Cholinesterase
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Ladostigil multifunctional drug derivative if rasagiline with a cholinesterase inhibitor moiety.
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For use in AD disease with Parkinsonism, Lewy body disease, and PD with dementia and depressive illness.
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It has been shown to have all the attributes of rasagiline as neuroprotective and neurorescue drug.
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It has antidepressant activity due to its MAO-A inhibitory activity.
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M30 and its Derivatives
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Multimodal drug iron chelator–radical scavenger MAO-AB inhibitor, M30, M30C and M30P, HLA20, HLA20A.
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For use in PD, AD, and ALS.
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Neuroprotective and neurorestorative.
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Neurotrophic activity, BDNF, VEGF, erythropoietin.
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Inhibitor of cyclin D1 resulting in cell differentiation.
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Monoamine Oxidase/A2A Antagonists
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Epidemiology has suggested caffeine use to be inversely related to PD.
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Dual MAO and A2A antagonists have been shown to be neuroprotective.
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NMDA/L-Type Calcium Channel Blockers
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Calcium overload in neuronal cells leads to cell death.
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Two major routes for calcium entry into cells are the NMDA receptor/ion channel as well as the L-type calcium channel.
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NGP1-01 is a dual-mechanism drug which blocks both the NMDA receptor/ion channel as well as the L-type calcium channel, with resulting neuroprotective activity shown in vivo.
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DAT inhibition by NGP1-01 may be additionally useful in treatment of the motor symptoms of PD.
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Green tea catechins
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Multimodal green tea polyphenols, EGCG have neuroprotective properties.
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Multiple neuroprotective mechanisms are suggested including antioxidant and metal chelation.
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Future perspective
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Multifunctional drugs show great promise as neuroprotective-neurorescue agents in neurodegenerative diseases.
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Multiple drug targets can be targeted with a single compound, with less chance of side-effects such as associated with the practice of polypharmacy.
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