Acetylcholinesterase inhibitors for Alzheimer s disease

Trabace, L., Cassano, T., Steardo, L., Pietra, C., Villetti, G., and Kendrick, K.M., Biochemical and neurobehavioural profile of CHF2819, a novel, orally active acetylcholinesterase inhibitor for Alzheimer s disease, /. Pharmacol. Exp. Therap., 294, 187-194, 2000. 

Cummings JL, Ringman JM. Metrifonate (Trichlorfon) a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer s disease. Expert Opin Investig Drugs 1999 8(4) 463-71. 

Benzazole scaffold A SWAT to combat Alzheimer s disease 13CSR7747. Coumarins as acetylcholinesterase inhibitors for Alzheimer s disease 12BMC1175. 

FIGURE 12—24. Icon for the cholinesterase inhibitor donepezil. This is the current first-line treatment for Alzheimer s disease, since it is a once daily agent without significant hepatotoxicity. It is a reversible agent, selective for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE), developed by American and Japanese companies. 

Neurotransmitters are removed by translocation into vesicles or destroyed in enzyme-catalysed reactions. Acetylcholine must be removed from the synaptic cleft to permit repolarization and relaxation. A high affinity acetylcholinesterase (AChE) (the true or specific AChE) catalyses the hydrolysis of acetylcholine to acetate and choline. A plasma AChE (pseudo-AChE or non-specific AChE) also hydrolyses acetylcholine. A variety of plant-derived substances inhibit AChE and there is considerable interest in AChE inhibitors as potential therapies for cognition enhancement and for Alzheimer s disease. Organophosphorous compounds alkylate an active site serine on AChE and the AChE inhibition by this mechanism is the basis for the use of such compounds as insecticides (and unfortunately also as chemical warfare agents). Other synthetics with insecticidal and medical applications carbamoylate and thus inactivate AChE (Table 6.4). 

Q6 Cholinesterase inhibitors block the action of the enzyme acetylcholinesterase (which normally hydrolyses acetylcholine) and so terminate its activity. These drugs increase the life of released acetylcholine at the synapse, leading to an enhancement of acetylcholine activity. Drug treatment for Alzheimer s disease is supervised in specialist clinics where the patient s cognitive function can be assessed at approximately three-monthly intervals. About half the patients treated show a decreased rate of cognitive decline while receiving this type of drug. 

Toda, N., Tago, K., Marumoto, S., Takami, K., Ori, M., Yamada, N., Koyama, K., Naruto, S., Abe, K., Yamazaki, R., Hara, T, Aoyagi, A., Abe, Y, Kaneko, T, Kogen, H. Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer s disease. Bioorg. Med. Chem. 2003, 11, 1935-1955. 

Du, D. M., Carlier, P. R. Development of bivalent acetylcholinesterase inhibitors as potential therapeutic drugs for Alzheimer s disease. Curr. Pharm. Des. 2004, 10, 3141-3156. 

There are no effective therapies for Alzheimer s disease and no cure. Treatment aims to enhance cholinergic transmission. The most useful drugs are central acetylcholinesterase inhibitors, for example donepezil. Acetylcholinesterase is the enzyme that normally breaks down acetylcholine after it has interacted with its receptors at the synapse. Inhibition of this enzyme in the brain increases the amount of acetylcholine available and prolongs its action. These drugs produce a modest improvement in memory or slow progression of symptoms in some patients. The response to anti-cholinesterase drugs may take several weeks. Their use is limited by side effects, which can be severe. 

Munoz-Torrero D (2008) Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer s disease. Curr Med Chem 15 2433-2455 Muntani G, Janue A, Fernandez N, Odena MA, Oliveira E, Boluda S, Portero-Otin M, Naudi A, Boada J, Pamplona R, Ferrer 1 (2010) Modification of brain lipids but not phenotype in alpha-synucleinopathy transgenic mice by long-term dietary n-3 fatty adds. Neurochem Int 12 Nov 2009 [Epub ahead of print]... 

Galanthamine para- ortho Narcissus pseudonarcissus Leucojum aestivum Galanthus niveali Galanthus elewesii Pancratium maritimum acetylcholinesterase inhibitor, treatment for Alzheimer s disease [4,8-10]... 

For the formal total synthesis of huperzine A (152), an acetylcholinesterase inhibitor and potential drug for Alzheimer s disease, several substrates with different substitution patterns... 

Wilkinson D, Roughan L (2007) The BRAINz trial a novel approach to acetylcholinesterase-inhibitor treatment for Alzheimer s disease. Future Neurol 2(4) 379-382. doi 10.2217/... 

Toda N, Kaneko T, Kogen H (2010) Development of an efficient therapeutic agent for Alzheimer s disease design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter. Chem Pharm Bull 58 273-287... 

Munoz-Torrero D (2008) Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer s disease. CurrMed Chem 15 2433-2455... 

Corey-Bloom J, Anand R, Veach J, for the ENA 713 B352 Study Group (1998). A randomised trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild and moderately severe Alzheimer s disease. IntJGeriatrPsychopharmacolX, 55-65. 

Table 10.4 Pharmacological properties of selected acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer s disease... 

Inhibitors of acetylcholinesterase are useful as pesticides and for treatment of Alzheimer s disease. In addition, they are chemical warfare agents. 

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