propargylamine and Neurodegenerative-Diseases

Much progress has been made in designing analogues that can potentially confer neuroprotection against debilitating neurodegenerative disorders, yet the multifactorial pathogenesis of this cluster of diseases remains a stumbling block for the successful design of an 'ultimate' drug. However, with the growing popularity of the "one drug, multiple targets" paradigm, many researchers have successfully synthesized and evaluated drug-like molecules incorporating a propargylamine function that shows potential to serve as multifunctional drugs or multitarget-directed ligands. It is the aim of this review to highlight the reported activities of these propargylamine derivatives and their prospect to serve as drug candidates for the treatment of neurodegenerative disorders.

Topics: Animals; Drug Discovery; Humans; Models, Molecular; Molecular Targeted Therapy; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Pargyline; Polypharmacology; Propylamines

Topics: Animals; Dopamine Agonists; Estradiol; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Pargyline; Propylamines

Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in rats and mice. However, their action on monoamine oxidase (MAO) A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and animal models of Parkinson's disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl, U74500A and U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B. Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) were time dependent and irreversible. Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were fully reversible by enzyme dilution experiments. Both Fe(2+) and Fe(3+) reverse the MAO-A and B inhibition induced by the latter chelators, but not those initiated by 21-amino steroids. The data infer that either the inhibition of MAO by 21-amino steroids is either the resultant of their conversion to an irreversible covalently bound ligand or that the iron chelation moiety and MAO inhibitory activity in these compounds are not mutually shared. The results suggest that bifunctional brain penetrable drugs with iron chelating property and MAO inhibitory activity in could be the most feasible approach for neuroprotection in neurodegenerative diseases. Such drug would prevent participation of elevated iron in oxidative stress and formation of reactive hydroxyl radical, via its interaction with H(2)O2 (Fenton chemistry), generated as a consequence MAO and other oxidative enzyme reactions to generative cytotoxic reactive hydroxyl radical. We have now developed several of these compounds with neuroprotective, MAO inhibitory and iron chelating properties from our prototype iron chelators, VK-28 possessing propargylamine moiety of our anti-parkinson drug, rasagiline.

Topics: Animals; Brain; Drug Delivery Systems; In Vitro Techniques; Indans; Iron Chelating Agents; Male; Mitochondria; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Pargyline; Parkinson Disease; Piperazines; Propylamines; Quinolines; Rats; Rats, Sprague-Dawley