Interaction with σ1 Protein, but Not N-Methyl-d-aspartate Receptor, Is Involved in the Pharmacological Activity of Donepezil

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 317; no. 2; p. 606
• Main Authors: Tangui Maurice, Johann Meunier, Bihua Feng, John Ieni, Daniel T. Monaghan
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.05.2006
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.097394

In the present study, we examined the interaction of (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1 H -inden-1-one hydrochloride (donepezil), a potent cholinesterase inhibitor, with two additional therapeutically relevant targets, N -methyl- d -aspartate (NMDA) and σ 1 receptors. Donepezil blocked the responses of recombinant NMDA receptors expressed in Xenopus oocytes. The blockade was voltage-dependent, suggesting a channel blocker mechanism of action, and was not competitive at either the l -glutamate or glycine binding sites. The low potency of donepezil (IC 50 = 0.7–3 mM) suggests that NMDA receptor blockade does not contribute to the therapeutic actions of donepezil. Of potential therapeutic relevance, donepezil binds to the σ 1 receptor with high affinity ( K i = 14.6 nM) in an in vitro preparation ( Neurosci Lett 260: 5–8, 1999). Thus, we sought to determine whether an interaction with the σ 1 receptor may occur in vivo under physiologically relevant conditions by evaluating the σ 1 receptor dependence effects of donepezil in behavioral tasks. Donepezil showed antidepressant-like activity in the mouse-forced swimming test as did the σ 1 receptor agonist igmesine. This effect was not displayed by the other cholinesterase inhibitors, rivastigmine and tacrine. The donepezil and igmesine effects were blocked by preadministration of the σ 1 receptor antagonist N -[2-(3,4-dichlorophenyl)ethyl]- N -methyl-2-(dimethylamino) ethylamine (BD1047) and an in vivo antisense probe treatment. The memory-enhancing effect of donepezil was also investigated. All cholinesterase inhibitors attenuated dizocilpine-induced learning impairments. However, only the donepezil and igmesine effects were blocked by BD1047 or the antisense treatment. Therefore, donepezil behaved as an effective σ 1 receptor agonist on these behavioral responses, and an interaction of the drug with the σ 1 receptor must be considered in its pharmacological actions.