General Description

Donepezil hydrochloride is a potent inhibitor of acetylcholinesterase, and its structure-activity relationships have been extensively studied. The presence of a carbonyl group in the indanone moiety and methoxy groups at specific positions enhance its potency. The linkage moiety between the indanone and piperidine moieties plays a critical role, with direct connection leading to decreased potency. The piperidine moiety, particularly the position of the nitrogen atom, is vital for activity. Substitutions at specific positions in the benzyl moiety can impact potency. In terms of pharmacological characteristics, Donepezil hydrochloride selectively inhibits acetylcholinesterase over butyrylcholinesterase, with consistent inhibitory activity across various sources of AChE. It exhibits significant neurochemical pharmacology in vivo, selectively inhibiting brain AChE compared to plasma AChE and elevating acetylcholine levels in the brain. Overall, donepezil hydrochloride is a potent and selective inhibitor of AChE with promising pharmacological characteristics.

Figure 1. Donepezil hydrochloride

Structure-Activity Relationships

Donepezil hydrochloride is a potent inhibitor of acetylcholinesterase and its structure-activity relationships have been extensively studied. Donepezil hydrochloride can be divided into four key parts: the indanone moiety, linkage moiety, piperidine moiety, and benzyl moiety. In terms of the indanone moiety, the presence of a carbonyl group in the indanone ring is crucial for activity, as shown by the decreased potency of indanol and indene derivatives. Introduction of methoxy groups at specific positions significantly enhanced activity, with para-position methoxy groups showing the greatest increase in potency. The linkage moiety between the indanone and piperidine moieties plays a critical role. Direct connection led to decreased potency, while varying lengths of bridging groups showed different effects on activity. The piperidine moiety is also vital, with the nitrogen atom's position being crucial for activity. Replacement with a piperazine group decreased potency, emphasizing the importance of the piperidine ring structure. Lastly, the benzyl moiety showed that substitutions at specific positions could impact potency, with certain groups enhancing or reducing activity. Donepezil hydrochloride, with its specific structural features, emerges as one of the most potent AChE inhibitors among the tested derivatives. ¹

Pharmacological Characteristics

Inhibition of cholinesterase in vitro

Donepezil hydrochloride demonstrates high selectivity and potent inhibition of acetylcholinesterase in vitro compared to butyrylcholinesterase. With an IC50 value of 6.7 nM for AChE and 7.4 μM for BuChE, donepezil's selectivity towards AChE is notable, especially when contrasted with tacrine, which inhibits both enzymes to a similar extent. The chemical structure of Donepezil hydrochloride, particularly its piperidine-based composition, contributes to its specificity for AChE. Unlike carbamate ChE inhibitors like physostigmine and rivastigmine, which require preincubation for full inhibition, donepezil shows consistent inhibitory activity across various sources of AChE, including electrical eels, rat brain homogenates, and human erythrocytes. Furthermore, Donepezil hydrochloride's mode of AChE inhibition is primarily noncompetitive, with some competitive characteristics. Its reversible inhibition is evidenced by the recovery of AChE activity after washing out, distinguishing it from irreversible inhibitors like diisopropylfluorophosphate. However, its efficacy against AChE solubilized for senile plaques suggests a potential variation in enzyme characteristics in pathological conditions. ²

Neurochemical pharmacology in vivo

Donepezil hydrochloride exhibits significant neurochemical pharmacology in vivo, particularly in its selective inhibition of brain acetylcholinesterase compared to plasma AChE. Oral administration of Donepezil hydrochloride demonstrates dose-dependent inhibition of brain AChE, with a minimal effective dose of 0.625 mg/kg and an ID50 value of 2.6 mg/kg. This suggests that donepezil is three to four times more potent in inhibiting brain AChE than tacrine. In aged rats as well as young rats, donepezil effectively inhibits brain AChE. In contrast, the action of Donepezil hydrochloride on plasma AChE is weaker, requiring higher doses (over 5 mg/kg) for significant inhibition. The favorable permeability of Donepezil hydrochloride to the brain, with concentrations 6 to 7 times higher in the brain compared to plasma, supports its central action as a centrally-acting inhibitor. Unlike tacrine and physostigmine, which inhibit both brain and peripheral tissues, donepezil shows selectivity for inhibiting brain AChE over peripheral tissues due to its preferential inhibition of AChE compared to butyrylcholinesterase. Furthermore, donepezil elevates acetylcholine content in hypocholinergic rat models by counteracting ACh depletion induced by scopolamine. It also dose-dependently increases ACh content in the cerebral cortex of rats, highlighting its efficacy in enhancing cholinergic neurotransmission in the brain. In vivo microdialysis studies demonstrate that Donepezil hydrochloride raises extracellular ACh levels in the cerebral cortex and hippocampus, correlating with its inhibitory effects on brain AChE. Compared to tacrine, Donepezil hydrochloride exhibits greater potency in increasing extracellular ACh levels in these brain regions. ²

Reference

1. Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn J Pharmacol. 2002;89(1):7-20.

2. Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem. 2000;7(3):303-339.