Executive Summary: Multimodal Drugs Under Development
  • 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 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.
RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2010 October; 1(2): e0011. ISSN: 2076-9172
Published online 2010 October 31. doi: 10.5041/RMMJ.10011.