Monoaminooxidases and Acetylcholinesterases 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.
More importantly, dual MAO and AChE inhibitors could show a uniquely favorable profile of pharmacologic action with an improved therapeutic window relative to single MAO or AChE inhibitors. Aims of this project are to design new inhibitors as therapeutic tools for neurodegenerative desorders and to perform a virtual screening for identifying new inhibitors ; to explore their hMAO-A and hMAO-B as well as AChE inhibitory potential respect to single-target inhibitors. The new produced molecules will be performed to define antioxidant activity.
Human monoamine oxidases (hMAOs) 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 . The two isoforms of these enzymes are called hMAO-A and hMAO-B, which 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. In the last years the investigations promoted the discovery of selective inhibitors for these enzymes. In fact, the use of non-selective MAO-inhibitors have limitations for the high prevalence of hMAO-A in the gastrointestinal tract where it is mainly involved in the metabolism of an exogenous monoamine, p-tyramine, that can behave as a peripheral adrenergic agonist and cause dangerous hypertensive crisis: the so called cheese-effect. In the light of the above even more researches worked towards the discovery of selective and reversible inhibitors for hMAO-B, highly expressed in neurodegenerative disease. 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 byproduct of MAO-catalyzed deamination of neurotransmitters, resulting in a neuroprotective and neurorestorative effects. Therefore, there is a considerable interest in obtaining potent and selective hMAO-B inhibitors.
AChE inhibitors, historically used for treatment of Alzheimer¿s disease, have received attention in the last years for their possible use in PD therapy. Acetylcholine and dopamine share several characteristics because both are involved in learning processes and cholinergic interneurons (CINs) of the striatum also undergo firing pattern changes during associative learning as do midbrain DA neurons .
Recently reported articles showed as anti-muscarinic compounds in the initial phase of PD can be useful to reduce extrapyramidal symptoms as well as the psychotic and cognitive disorders associated with PD, without exacerbating motor symptoms. Keeping in mind all this information, the discovery of dual-target inhibitors could represent a step forward for the development of new and useful therapies for PD and AD.