Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

Abstract

Summary:The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(Npropargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuroprotective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer's disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagilinecontaining hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer's disease.

Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease

“…Although selegiline, the first selective inhibitor of MAO-B, has been widely used in patients with PD as monotherapy and adjuvant therapy, its basic and clinical pharmacological effects have not yet been fully elucidated. There is evidence that its neuroprotective characteristics are mediated through its effects on protein kinase C and mitogen-activated protein kinase signaling pathways (5). Indeed, the improvements observed as regards clinical PD progression following the use of this type of drug have confirmed its neuroprotective activities, which have been previously reported in various cell culture and preclinical in vivo models (6)(7)(8)(9)(10).…”

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…Increased oxidative stress in patients with AD contributes to Aβ generation and the formation of amyloid plaques. It has been established that MAO, a marker of oxidative stress, is linked to the production of reactive oxygen species and other molecules that cause oxidative stress, which results in neuronal damage and neurodegeneration, including AD, indicating that excessive MAO activity contributes to neurodegeneration in AD (62,(111)(112)(113). Molecular biology studies have shown the critical role of Aβ generation through the modulation of APP processing by MAO (60,61,114,115) (Fig.…”

“…An increasing number of molecular biology and pharmacology studies have shown the neuroprotective effects of MAO inhibitors on the prevention and treatment of AD (21,52,53) (Table I) (15,56,57,61,62,112,114,(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). The main neuroprotective mechanisms of MAO inhibitors in AD include the following: i) Improvement of cognitive impairment (50,54,55), where MAO inhibitors correct chemical imbalances in the brain; ii) antioxidant activities and enhancement of iron-chelating activities (56)(57)(58)(59), where chelators can modulate Aβ accumulation, protect against tau hyperphosphorylation and block metal-associated oxidative stress, thereby holding considerable promise as effective anti-AD drugs (145,146); iii) regulation of APP and Aβ expression processing (56,60), for example ladostigil (TV3326), a selective MAO-B inhibitor, which regulates APP translation and processing (114); iv) the selective MAO inhibitors selegiline and rasagiline have been proven to possess neuroprotective activities in cell cultures and animal models of neurodegenerative diseases through the activation of certain signaling pathways, including p42/44 MAPK and PKC (61); v) inhibition of ChE activity by the MAO inhibitor rasagiline (62)(63)…”

Design, Synthesis, and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium‐like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors

“…[15a, 21] In this emerging and challenging scenario, many multifunctional molecules have been reported in which AChE inhibitor fragments (generally but not exclusively from tacrine, (À)-huperzine A, and close analogues) were conjugated with a molecular moiety profiling the adjunctive targeted activity (e.g., antioxidant, [22] metal chelating, [23] neuroprotective, [17,18,24,25] and anti-amyloidogenic [16c, 26] ). In the latter case, the design rationale lies in the well-known implication of the PAS of AChE in promoting the aggregation of Ab into senile plaques.…”