The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30.
The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin.
Youdim
Moussa B H
MB
Eve Topf Centres of Excellence for Neurodegenerative Diseases Research, Technion-Rappaport Family Faculty of Medicine and Department of Pharmacology, Haifa, Israel. youdim@tx.technion.ac.il
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000627:therapeutic use; D007189:Indans / Q000737:chemistry / Q000627:therapeutic use; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D012642:Selegiline / Q000737:chemistry / Q000627:therapeutic use
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D000978:Antiparkinson Agents; D006912:Hydroxyquinolines; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D012642:Selegiline