Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

“…Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the upcoming years. Other targets relevant to AD have also been considered in the last years for making multitarget compounds [11,12].…”

“…Considering the current hypothesis of accretion of the Aβ in AD, this relies in the reduction of acetylcholine release in central cholinergic nervous system involved in cognitive function. Thus, the inhibition of acetylcholine degradation by AChE is a potential goal to treat AD [11,12]. Deleterious excess Ca 2+ influx is also another constituent seen in aging and neurodegenerative diseases [13].…”

“…Deleterious excess Ca 2+ influx is also another constituent seen in aging and neurodegenerative diseases [13]. Thus, hybrid compounds having the moieties of tacrine (potent inhibitor of brain and peripheral AChE), and nimodipine (L-type CCBs) have been synthetized [11,12]. In addition, galantamine, a mild AChE inhibitor, and an allosteric ligand of nicotinic receptors, has been used to progress enhancing cognition and behavior in patients with AD [14].…”

Understanding Acetylcholinesterase Inhibitors: Computational Modeling Approaches

“…The accumulation of these plaques is considered neurotoxic; 14,30,31,35,38,41,44,45 -formation of neurofibrillary tangles. These tangles are composed by filaments formed in the hyperphosphorylation of the tau protein within neurons (intracellular) and its branches projections (axons and dendrites) mainly in the cerebral cortex, specifically at pyramidal neurons, temporal lobe, the hippocampus and amygdale; 14,30,31,35,38,44 -sharp decrease in the amount of neurotransmitters in the synaptic regions. The acetylcholine (ACh), serotonin, dopamine, noradrenaline, and P substance are the neurotransmitters whose frequently diminish in AD processes.…”

“…51,52 In the amyloid hypothesis the deposit of senile plaques produced mainly by beta-amyloid protein can be avoided by using drugs that inhibit its excessive production in synapse. 33,35,44,45,53 This hypothesis is viewed with certain caution, since tests on rats and mice have revealing is not always true that animals who develop amyloid plaques will develop AD. 33,54,55 The oxidative stress therapy proposes that metal (Fe, Cu, and Zn) ions may crucially participate in the pathological process of AD.…”