Recent Patents on CNS Drug Discovery, 2009, 4, 43-51 43 1574-8898/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd. Contemporary Anticholinesterase Pharmaceuticals of Natural Origin and Their Synthetic Analogues for the Treatment of Alzheimer’s Disease Gürdal Orhan 1 , Ilkay Orhan 2, *, Nee Subutay-Öztekin 1 , Fikri Ak 1 , Bilge ener 2 1 Neurology Clinic, Numune Educational and Research Hospital, The Ministry of Health, Ankara 06100, Turkey, and 2 Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, 06330, Turkey Received: August 4, 2008; Accepted: September 25, 2008; Revised: September 29, 2008 Abstract: Alzheimer’s disease (AD), the most common form of dementia, is a degenerative and progressive neurological disorder characterized by deficit in the cholinergic transmission and formation of senile plaques containing -amyloid protein in the brain. Although complete pathology of the disease has not been fully elucidated yet, there are several treatment strategies for AD treatment. The complexity of AD is also due to involvement of several enzymes through its progression. Therefore, the most important therapeutic approach has emerged as inhibition of acetylcholinesterase (AChE), which is the key enzyme in the breakdown of acetylcholine. Another very attractive approach to lower -amyloid protein in fibrillar form has been the - and -secretase inhibitors. On the other hand, recently, N-methyl-D-aspartate (NMDA) receptor antagonists have become a strong alternative, which has been approved to be effective in treatment of moderate to severe type of AD. Within the past few years, some pharmaceuticals have become available for clinical use; however, none of them have been shown to possess ability to discontinue the disease up to date. Hence, there is obviously a great need for discovery of new drug candidates of natural or synthetic origins for AD treatment. This review will cover AChE-inhibiting pharmaceuticals from plants and their synthetic derivatives including relevant patent literatures which may promise a future hope for AD treatment. Keywords: Alzheimer’s disease, dementia, acetylcholinesterase, acetylcholinesterase inhibitors, physostigmine, galanthamine, huperzine A, plants. INTRODUCTION Alzheimer’s disease (AD) is a neurodegenerative and progressive disorder of the brain characterized by memory loss and impairment in behavior. It is one of the most threatening diseases to the elderly population with an increasing incidence, particularly in western countries and the USA. [1]. The prevalence of the disease is being expected to rise drastically in the next decades [2]. In fact, AD is the most common neurodegenerative disease in the US whose prevalence over four million patients currently [3]. Although etiology of AD has not been fully elucidated yet, modern treatment strategies typically comprise of anti- cholinesterases, antioxidants, - and -secretase inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists. Recently, neuroinflammation has been also found to be associated with the possible progression of neurodege- nerative diseases [4]. Among these drug classes, the most luminous ones appear to be AChE inhibitors depending on their effectiveness; however, they still do not change the rate of development of neurodegeneration because of the progressive nature of AD. The disease may vary from moderate to mild, and finally severe-types. At the moment, unfortunately, there is no cure available to impede the severe-type of AD whereas only symptomatic treatment is applicable for the moderate and mild-types, which often lasts about 2-3 years. *Address correspondence to this author at the Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, 06330, Turkey; Tel: +90.312.2023186; Fax: +90.312.2235018; E-mail: iorhan@gazi.edu.tr AChE inhibitors (or anticholinesterases) have aptitude to inhibit the hydrolysis of the neurotransmitter called acetyl- choline and elevate its level in the synaptic cleft. Interestingly, the data also designate that the enzyme AChE possesses some additional functions besides their role in terminating the action of acetylcholine at the cholinergic synapses. For instance; the pure form of AChE isolated from the electric eel (Electrophorus electricus) shows aryl acyl- amidase activity which is perceptive to serotonin [5]. This activity has been also established in AChE from different biological sources such as human serum, erythrocyte, liver, and sheep basal ganglia [6,7]. There have been many acetylcholinesterase (AChE) inhibitors of natural and synthetic origins emerging on the market and they have been the subjects of the researchers focused on drug development for AD. In this review, information about modern AChE inhibitors from plants and their future-promising synthetic analogues are summarized. PHYSOSTIGMINE AND ITS DERIVATIVES AD treatment was firstly started with use of physostigmine (1) as its salicylate or sulphate salt, being the first AChE inhibitor, in early 1890’s [8,9]. Physostigmine [1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-N-methylcarba- mate, (3aS,8aR)-pyrrolo(2,3-b)indol-5-ol] Fig. (1) is a para- sympathomimetic plant alkaloid isolated from the seeds of Physostigma venenosum Balf of Fabaceae family, which is known as “Calabar bean”. Actually, the extract of Calabar bean was to start with practice as atropine antidote in 1860’s [10,11]. Physostigmine, also named as “eserine”, was firstly synthesized in 1935 in Minshall Laboratory (USA) by the