Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

https://jnnp.bmj.com/content/jnnp/66/2/137.full.pdf

The cholinergic hypothesis of Alzheimer’s disease: a review of progress

Quantitative structure-activity and structureproperty relationship (QSAR/QSPR) studies are unquestionably of great importance in modern chemistry and biochemistry. The concept of QSAR/QSPR is to transform searches for compounds with desired properties using chemical intuition and experience into a mathematically quantified and computerized form. Once a correlation between structure and activity/property is found, any number of compounds, including those not yet synthesized, can be readily screened on the computer in order to select structures with the properties desired. It is then possible to select the most promising compounds to synthesize and test in the laboratory. Thus, the QSAR/QSPR approach conserves resources and accelerates the process of development of new molecules for use as drugs, materials, additives, or for any other purpose. While it is not easy to find successful structureactivity/property correlations, the recent exponential growth in the number of papers dealing with QSAR/ QSPR studies clearly demonstrates the rapid progress in this area. To obtain a significant correlation, it is crucial that appropriate descriptors be employed, whether they are theoretical, empirical, or derived from readily available experimental characteristics of the structures. Many descriptors reflect simple molecular properties and thus can provide insight into the physicochemical nature of the activity/ property under consideration. Recent progress in computational hardware and the development of efficient algorithms has assisted the routine development of molecular quantummechanical calculations. New semiempirical methods supply realistic quantum-chemical molecular quantities in a relatively short computational time frame. Quantum chemical calculations are thus an attractive source of new molecular descriptors, which can, in principle, express all of the electronic and geometric properties of molecules and their interactions. Indeed, many recent QSAR/QSPR studies have employed quantum chemical descriptors alone or in combination with conventional descriptors. Quantum chemistry provides a more accurate and detailed description of electronic effects than empirical methods.1 Quantum chemical methods can be applied to quantitative structure-activity relationships by direct derivation of electronic descriptors from the molecular wave function. In many cases it has been established that errors due to the approximate nature of quantum-chemical methods and the neglect of the solvation effects are largely transferable within structurally related series; thus, relative values of calculated descriptors can be meaningful even though their absolute values are not directly applicable.2 Moreover, electronic descriptors derived from the molecular wave function can be also partitioned on the basis of atoms or groups, allowing the description of various molecular regions separately. Most work employing quantum chemical descriptors has been carried out in the field of QSAR rather than QSPR, i.e. the descriptors have been correlated with biological activities such as enzyme inhibition activity, hallucinogenic activity, etc.3-6 In part this has been because, historically, the search for quantitative relationships with chemical structure started with the development of theoretical drug design methods. Quantum-chemical descriptors have also been reported to correlate the reactivity of organic compounds, octanol/water partition coefficients, chromatographic retention indices, and various physical properties of molecules.7-11 The present article reviews applications of quantum chemical descriptors in the development of QSAR/QSPR dealing with the chemical, physical, biochemical, and pharmacological properties of compounds.

http://depa.fquim.unam.mx/amyd//archivero/TrabajoFINAL2013-1_21514.pdf

Quantum-Chemical Descriptors in QSAR/QSPR Studies

The cholinergic hypothesis of alzheimer's disease : a review of progress. authors' reply

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Epidemiological studies have revealed that a diet rich in plant-derived foods has a protective effect on human health. Identifying bioactive dietary constituents is an active area of scientific investigation that may lead to new drug discovery. Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many edible plants (e.g. tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries and grapes) and in plants or botanical products commonly used in traditional medicine (e.g. Ginkgo biloba, Tilia spp, Equisetum spp, Moringa oleifera, Sophora japonica and propolis). Some epidemiological studies have found a positive association between the consumption of foods containing kaempferol and a reduced risk of developing several disorders such as cancer and cardiovascular diseases. Numerous preclinical studies have shown that kaempferol and some glycosides of kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anticancer, cardioprotective, neuroprotective, antidiabetic, anti-osteoporotic, estrogenic/antiestrogenic, anxiolytic, analgesic and antiallergic activities. In this article, the distribution of kaempferol in the plant kingdom and its pharmacological properties are reviewed. The pharmacokinetics (e.g. oral bioavailability, metabolism, plasma levels) and safety of kaempferol are also analyzed. This information may help understand the health benefits of kaempferol-containing plants and may contribute to develop this flavonoid as a possible agent for the prevention and treatment of some diseases.

A review on the dietary flavonoid kaempferol.

Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.

http://www3.uah.es/farmamol/Public/Curr_Med_Chem/donepezil_CMC2000.pdf

Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors.

Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer's disease. To elucidate whether donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamate-free medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of donepezil in a concentration-dependent manner. Among AChE inhibitors examined, donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-beta-erythroidine, an alpha4beta2-neuronal nAChR antagonist, and methyllycaconitine, an alpha7-nAChR antagonist, each also significantly antagonized the effect of donepezil. Next, we examined the effects of donepezil on glutamate-induced apoptosis. Exposure of 100 microM glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that donepezil not only protects cortical neurons against glutamate neurotoxicity via alpha4beta2- and alpha7-nAChRs but also prevents apoptotic neuronal death.

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

https://www.jstage.jst.go.jp/article/jjp/89/1/89_1_7/_pdf

Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor.

A cyclic amine compound is defined by the formula: ##STR1## in which J is indanyl, indanonyl, indenyl, indenonyl, indanedionyl, tetralonyl, benzosuberonyl, indanolyl or a divalent group thereof, K is phenyl, an arylalkyl or cynnamyl, B is --(CHR22)r--, R22 being H or methyl, --CO--(CHR22)r--, ═(CH--CH═CH)b--, ═CH--(CH2)c-- or ═(CH--CH)d═ and the ring including T and Q is piperidine. The compound is useful to treat senile dementia.

Hachiro Sugimoto

Papers

Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds

Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors.

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor.

Cyclic amine compounds with activity against acetylcholinesterase