The Practical Pharmacology of Donepezil

Abstract

From 1976 to 1977, three British groups established the acetylcholine (ACh) hypothesis, which claims that the activity of choline acetyltransferase (ChAT), an ACh synthase, is decreased in the brains of patients with Alzheimer’s disease (AD), causing a disorder in their cholinergic system with the decline in ACh (Bowen et al. 1976; Davies and Maloney 1976; Perry et al. 1977). Consequent to this development, researchers felt that replenishing ACh might treat AD. They attempted a treatment method involving supplementation of substances that serve as raw materials for ACh synthesis. ACh synthesis was expected to be catalyzed by ChAT from choline supplied from outside the brain and acetyl CoA produced inside the brain. Therefore, a clinical trial of choline administration using lethicin was conducted. However, the efficacy of this treatment could not be confirmed. Next, a method was contrived to increase ACh in the synaptic cleft by inhibiting ACh esterase (AChE), an ACh-degrading enzyme (Fig. 2.1). Physostigmine, an alkaloid, shows AChE inhibitory activity. A clinical research study was also reported the use of tacrine as an AChE inhibitor (Summers et al. 1986). However, these drugs received poor clinical assessments. One reason was that physostigmine is an extremely unstable compound, and the other was tacrine-induced serious liver dysfunction.