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