Send Orders for Reprints to [email protected] 366 Frontiers in Drug Design & Discovery, Vol. 6, 2014, 366-386 CHAPTER 6 Specific Cholinesterase Inhibitors: A Potential Tool to Assist in Management of Alzheimer Disease Nigel H. Grieg1, Mohammad A. Kamal2,*, Nasimudeen R. Jabir2, Shams Tabrez2, Faizul H. Nasim3, Adel M. Abuzenadah2 and Gjumrakch Aliev4,5 1Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; 2King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; 3Department of Chemistry, BJ Campus, The Islamia University of Bahawalpur, Bahawalpur, Pakistan; 4Department of Health Science and Healthcare Administration, University of Atlanta, Atlanta, GA, USA, and 5GALLY International Biomedical Research Consulting LLC, San Antonio, TX, USA Abstract: Accompanying the gradual rise in the average age of the population of most industrialized countries is a regrettable escalation in individuals afflicted with progressive neurodegenerative disorders, epitomized by Alzheimer's disease (AD). The development of effective new treatment strategies for AD has therefore become one of the most critical challenges in current neuroscience. Cholinesterase inhibitors (ChEIs) remain the primary therapeutic strategy for AD, and act by amplifying residual cholinergic activity, a neurotransmitter system central in cognitive processing that is reported to be depleted in the AD brain. With the recent failure of current drug classes focused towards the molecular events known to underpin AD, including the generation of amyloid-β peptide (Aβ) containing plaques and neurofibrillary tangles (hyper- phosphorylated tau). The development of new generation of cholinergic drugs has been accomplished to take advantage of the known modulatory action of the cholinergic system on Aβ, tau production as well as the maintenance synapses, which are known to be lost in AD. Following upon the development of acetylcholinesterase inhibitors (AChE-Is), phenserine, that additionally possessed amyloid precursor protein (APP) synthesis inhibitory actions to lower the generation of Aβ. Selective butyrylcholinesterase inhibitors (BuChE-Is), cymserine analogues, have been developed on the same chemical backbone during further anti-AD research advancement. The above mentioned inhibitors retain actions on APP as well as Aβ and amplify central cholinergic actions without the classical dose-limiting adverse effect profile; therefore, these current BuChE-Is are now moving into AD clinical trials. *Address correspondence to Mohammad A. Kamal: Metabolomics and Enzymology Unit, Fundamental and Applied Biology, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Tel: +612-98644812; Fax: +15016368847; E-mail: [email protected] Atta-ur-Rahman / M. Iqbal Choudhary (Eds.) All rights reserved-© 2014 Bentham Science Publishers Specific Cholinesterase Inhibitors Frontiers in Drug Design & Discovery, Vol. 6 367 Keywords: Acetylcholinesterase, acetylcholinesterase inhibitors, Alzheimer disease, amyloid-β peptide, amyloid precursor protein, butyrylcholinesterase inhibitors, cholinesterases, clinical trials, cymserine, dementia, glial cells, inhibitors, kinetic analysis, muscle disorders, neurodegenerative disorders, neurotransmitters, synaptic cleft, tau protein. INTRODUCTION A significant segment of career of several scientists’ in the field of anti- Alzheimer's research is spending in elucidating the interaction of various anti- Alzheimer agents on the key enzyme acetylcholinesterase (AChE), which is fundamental to nervous system function and life. There are various challenging tasks in the development of the novel drug such as in case of phenserine from laboratory to the clinic by Nigel H Greig. Specifically, the essential elucidation of the kinetics of particular agent's interaction with AChE or butyrylcholinesterase (BuChE) become the base in its application and approval for an Investigational New Drug Application by the United States Government Food and Drug Administration (US-FDA) to allow the use of the compound in humans to assess its utility in the treatment of Alzheimer's dementia. It is worthwhile, to mention in a similar manner, Greig's and his colleagues studied in the development of novel agents such as cymserine and analogues, to test the radically new hypothesis that selective BuChE inhibition is of value in the therapy of Alzheimer's disease (AD). Drugs of this class are currently in preclinical development and are expected to translate into the clinic soon. There are several research articles available in the literature related with kinetic analysis for such type of new agents such as tetrahydro-furobenzofuran cymserine, a potent BuChE inhibitor and experimental Alzheimer drug candidate [1]. Mostly these types of agents are focused on syntheses of specific carbamates related to physostigmine to figure out their anticholinesterase activities and action on amyloid precursor protein (APP). According to one study, administration of AChE inhibitors increases the ratio of APP forms in platelets of patients with AD, suggesting a potential effect of AChE inhibitors (AChE-Is) on APP trafficking or processing in a peripheral cell [2]. Overall, the conclusive progress of inhibitors of cholinesterases (ChEIs) involved in the cognitive responses, i.e. AD management is still under progress due to various factors such as variability in ChEIs treatment. 368 Frontiers in Drug Design & Discovery, Vol. 6 Grieg et al. ALZHEIMER'S DISEASE Consequent to improvements in preventative, diagnostic and medical treatment for cardiovascular and oncological diseases, the mean age of most industrialized countries humans, continues to steadily climb. Sadly, allied with this rise in life span there has been a steady increase in the number of individuals afflicted with age-related debilitating neurodegenerative disorders, in particular AD. Indeed, in excess of 20 million people worldwide are afflicted with AD. Neurodegenerative diseases are not only amongst the most common causes of death but are currently among the most debilitating illnesses and force an enormous strain, not only on the afflicted and their families, but on both social and healthcare budgets throughout the world. In case of the AD brain, neural dysfunction allied to the induction of numerous biological cascades that cause the classical pathological hallmarks of disease. This is characterized by the presence of (i) amyloid deposits, extra-neuronally, that contain a small toxic cleavage product of APP processing, (ii) neurofibrillary tangles, intra-neuronally, that comprise of hyperphosphorylated tau and, (iii) a dramatic synaptic loss. Of the neurotransmitters involved, the cholinergic system is the earliest and most affected, and hence has received the greatest attention with regard to drug design and development. The primary therapeutic strategy, to date, involves the use of ChEIs to amplify remaining cholinergic activity, which improve cognition and global performance and reduce psychiatric and behavioral disturbances. AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy; primarily with AChE-Is to amplify remaining cholinergic activity. The first ChEIs approved for AD treatment was, tacrine (Cognex) in 1993, but it was proved to be relatively short-acting, unselective between the two ChE enzymes, and associated with a high incidence of reversible hepatotoxicity. In contrast, the second generation ChEIs, donepezil hydrochloride (Aricept), rivastigmine (Exelon) and galatamine (Reminyl), approved by US-FDA in the year 1996, 2000 and 2002 respectively, remain in current use, are better tolerated and have been found useful in treating mild to moderate AD patients. However, these improvements are unfortunately, quite modest. In fact, recent clinical trials have triggered considerable controversy concerning the relevance and the benefit of this class of drugs. Such concern has instigated two avenues of Specific Cholinesterase Inhibitors Frontiers in Drug Design & Discovery, Vol. 6 369 research. One to develop a new class of ChEIs with activity beyond the modest symptomatic one associated with initial agents, and another to optimize current agents based on a greater understanding of enzyme/inhibitor interactions. New agents that can affect disease progression are sorely needed. Cholinergic loss is the single most replicated neurotransmitter deficiency in AD and has led to the use of AChE-Is as the mainstay of treatment [1]. AChE-Is, however, induce dose- limiting adverse effects [1]. Inhibition of brain BuChE represents a new drug target for AD treatment. Current studies indicated that selective BuChE-Is elevate acetylcholine (ACh) in brain, which augment long-term potentiation and improve cognitive performance in rodents without the classic adverse effects of AChE-Is. BuChE-Is thereby represent a new strategy to ameliorate AD, particularly since AChE activity is depleted in AD brain, in line with ACh levels, whereas BuChE activity is elevated [1]. The BuChE to AChE ratio hence changes dramatically in cortical regions affected by AD from 0.2 up to as much as 11. This altered ratio in AD brain likely modifies the normal role of BuChE in the nervous system of hydrolyzing, excess ACh to depleting already reduced levels of the neurotransmitter. TYPES