Monoaminooxidases and Cholinesterases plays a significant role in neurodegenerative desorders. Due to this relevant role in Alzheimer (AD) and Parkinson's Disease's (PD), a number of inhibitors has been reported to date. Rational molecular design, target recognition and predicted pharmacokinetic properties will be evaluate by means of molecular modelling. Base on these properties, compounds will be synthesize and evaluate in vitro as MAO-B and ChE inhibitors, and compare to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively.
Innovatività della ricerca, e potenzialità di realizzare un avanzamento delle conoscenze rispetto allo stato dell'arte / Innovation of the research and possible progress beyond the State of the Art /5000
AChE inhibitors are historically used for treatment of Alzheimer's disease being able to restore the cholinergic tone impaired in this illness. The FDA approved drugs Donepezil, Rivastigmine and Galantamine, possess some structural motifs that can be exploited in order to develop novel and potent agents endowed with multifunctional properties. Indeed, oxidative stress, proteins misfolding and aggregation, excitotoxicity, neuroinflammation, and neuronal loss are common in neurodegenerative disorders. As a consequence, the ability of one compound to act simultaneously against different insulting agents can improve dramatically the therapeutic outcomes. In this regards, human monoamine oxidases (hMAOs) can play an important role. Human monoamine oxidases are FAD-dependent enzymes involved in the oxidative deamination of endogenous and exogenous primary, secondary and tertiary amines including several neurotransmitters, to the corresponding imines. These enzymes are located on the outer mitochondrial membrane and play a fundamental physiological role in monoaminergic neurotransmissions regulation by controlling the amounts of dopamine (DA), adrenaline (A) and noradrenaline (NA) inside the synaptic cleft [1]. The two isoforms of these enzymes called hMAO-A and hMAO-B, differ in distribution and substrate specificity. Another difference between the two enzymes is the sensibility to inhibitors used for the treatment of diseases that result from deficient neurotransmitter levels with the impairment of synaptic transmission, such as depressive disorders and neurodegenerative diseases. Furthermore hMAO-B is highly expressed in neurodegenerative diseases. hMAO-B selective inhibition is expected to enhance dopaminergic neurotransmission, which is beneficial for Parkinson¿s disease (PD), and to reduce the oxidative stress exerted on neurons by hydrogen peroxide, a by-product of MAO-catalyzed deamination of neurotransmitters, resulting in a neuroprotective and neurorestorative effects, that instead is useful for AD.
Keeping in mind all this information, the discovery of dual-target inhibitors could represent a step forward for the development of new and effective therapy for AD.