A Step Further Towards Multitarget Drugs for Alzheimer and Neuronal Vascular Diseases: Targeting the Cholinergic System, Amyloid-β Aggregation and Ca2++ Dyshomeostasis

R.      Leon; J.      Marco-Contelles

doi:10.2174/092986711794480186

Abstract

Alzheimers disease (AD) is the most common neurodegenerative disease, affecting mainly elderly people. The reasons why AD occurs are complex and multifactorial and several biochemical targets are thought to play a key role in its progress and development. This fact has led to the development of a multitarget-directed ligand strategy as a logical approach for designing a suitable therapy. Currently, most prescribed drugs for treating AD are acetylcholinesterase inhibitors (AChEI), although these inhibitors represent solely palliative treatment. This account will summarize our current therapeutic approach for the design of multitarget drugs primarily aimed at inhibiting AChE using the key features of tacrine, which was the first approved drug for AD treatment. Secondly, as calcium homeostasis is directly related to the cell death-survival equilibrium, suitable therapy might include an action that regulates calcium homeostasis by means of targeting voltage dependent calcium channels. It is, therefore, hoped that targeting calcium homeostasis will lead directly to the development of potential neuroprotective agents. Thus, 1,4-dihydropyridines, well-known voltage-dependent calcium channel (VDCC) ligands, will be incorporated into the new molecules as a second structural feature in order to bring about this action. As a result of this development, herein, we describe the synthetic and pharmacological profile of new [1,8]-naphthyridine analogues, which are hybrids of tacrine and 1,4-dihydropyridines. Some of our molecules have shown improved inhibitory action against cholinesterases, whilst maintaining their VDCC modulating activity, and have good characteristics as neuroprotective agents. Based on kinetic analysis of the AChE inhibition experiments, it has been shown that many of the compounds bind at the peripheral anionic site (PAS). Since the AChE PAS is linked to β-amyloid aggregation, this would give a third biological target for further preclinical development, making these molecules highly interesting targets in the search to obtain better treatments for AD.

Keywords: Alzheimer's disease, multitarget drugs, AChE inhibition, AChE peripheral anionic site, Ca2+ dyshomeostasis, 1,4- dihydropyridines, voltage dependent calcium channels, amyloid β, neuroprotection, Ca2+ overload, Neuronal Vascular Diseases, Cholinergic System, oxidative stress, neurodegenerative diseases (NDDs), World Health Organization, dementia, aphasia, agnosia, apraxia, acetylcholine (ACh), nicotinic acetylcholine receptors, hypotheses, amyloid hypothesis, cho-linergic hypothesis, apolipoprotein E, brain parenchyma, tau hyperphosphorylation, reactive oxygen species, multitarget-directed-ligands, hepatotoxicity, arylidenemalononitriles, pyranotacrines, Tacrine, Tacripyrines, Nimodipine