Medicinal chemistry approaches for the treatment and prevention of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites.

Bioactive compounds from endemic plants of Southwest Portugal: Inhibition of acetylcholinesterase and radical scavenging activities

“…Alterations produced by neuropathologies include oxidative stress markers (Andersen, 2004) as well as the decline in cognitive function associated with cholinergic deficits (Bachurin, 2003). The limited resources for combating oxidative stress by the central nervous system include the following: Vitamins, bioactive molecules, lipoic acid, antioxidant enzymes and redox sensitive protein transcriptional factors.…”

“…Acetylcholinesterase (AChE) inhibition may help in the treatment of Alzheimer's disease (AD) as well as senile dementia, myasthenia gravis (Thanvi & Lo, 2004), Parkinson's disease (Soreq & Seidman, 2001) and ataxia (Mukherjee et al, 2007a) due to the associated cholinergic deficit (Bachurin, 2003). Few of this class of inhibitors have yet been approved for AD therapy (Bachurin, 2003) and most of them have short half-life and peripheral cholinergic side effects (Fang et al, 2008;Mukherjee et al, 2007b;Nordberg & Svensson, 1998;Perry et al, 2003) which significantly limit its therapeutic use.…”

Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression

“…Dimebon, a tetrahydro-g-carboline with anti-histamine effects, was reported to block the apoptosis of cortical neurons (Bachurin et al, 2001), protect the mitochondrial membrane potential Pieper et al, 2010), promote neurite outgrowth in cultured hippocampal and cortical neurons Bernales et al, 2009), dose-dependently increase neurogenesis in the rat dentate gyrus (Pieper et al, 2010), act in vitro as a low-affinity NMDA receptor blocker via the NR2B subunit (Perlovich et al, 2009) and enhance memory properties in middle-aged mice (Vignisse et al, 2011). The role of these factors in the neurobiology of depression was generally documented (Skolnick et al, 2009;Pittenger and Duman, 2008;Marcocci et al, 2002), however, it remains to be studied whether dimebon may exert any systemic effects via these mechanisms (Bachurin, 2003).…”

Synthesis of some tetrahydropyrimidine-5-carboxylates, determination of their metal chelating effects and inhibition profiles against acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase

“…Crystalline compound holds two crystallographical independent molecules. [100][101][102] . However, during the progression of AD, brain AChE levels decline while BChE activity increases, suggesting that ACh hydrolysis may occur to a greater extent via BChE catalysis.…”