Cholinesterase Inhibitors and Beyond

Abstract

Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineteen nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under 'ChEI' for 1995-2007. The list is reduced to 2500 if we confine ourselves to 'ChEIs and dementia'. Of them, about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, the clinical effectiveness of ChEIs has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is not cost effective, with benefits below a minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for acetyl- (AChE) and butyrylcholinesterase (BuChE). The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the "classical" ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and particularly the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

“…Acetylcholinesterase inhibitors (AChEIs) exert their therapeutic action by inhibiting AChE, which results in the enhancement of cholinergic action 2 . In particular, AChEIs play a leading role in the first-line treatment for symptoms of Alzheimer's disease, which is the most common age-related neurodegenerative disorder [5][6][7][8][9] .…”

Scopolamine-induced learning impairment reversed by physostigmine in zebrafish

“…By way of contrast, muscarinic receptor agonists such as pilocarpine have been demonstrated to reduce scopolamine-induced impairments in avoidance response (De-Mello et al, 2005). AChE inhibitors such as rivastigmine, donepezil, and galantamine are all used to improve memory deficits in humans and animals (Saxena et al, 2008;Benetti et al, 2009;Pepeu and Giovannini, 2009). The inhibition of acetylcholinesterase (AChE) which breaks acetylcholine down into acetyl CoA and choline, increases acetylcholine levels in the synaptic cleft, and thus enhances cholinergic transmission, which leads to improvements in learning and cognitive deficits.…”

Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines

“…Recent studies have shown that BuChE exerts an influence on the modulation of motor control, awareness, cognition and behavior by regulation of ACh levels in the central nervous system (CNS) 26 . Both enzymes remain valuable targets in anti-AD drug discovery studies [27][28][29][30] . Many selective or dual acting inhibitors of both enzymes were developed 31,32 , and among them compounds which display activity also on Ab aggregation and neurofibrillary tangles [33][34][35][36][37] .…”