Anavex Life Sciences Corp (AVXL)

[Investor2014]

Seem like Sigma-1 receptor agonism may have been an unintended side action of Donepezil, which although not fully understood is thought to have its (limited) effect based on being a centrally acting reversible acetylcholinesterase inhibitor.

There is however research that shows that what little effect Donepezil has may actually instead be related to its Sigma-1 agonism. Perhaps our Anavex-now Mono style advocates have a point.

Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil.

Thus, we sought to determine whether an interaction with the sigma(1) receptor may occur in vivo under physiologically relevant conditions by evaluating the sigma(1) receptor dependence effects of donepezil in behavioral tasks. Donepezil showed antidepressant-like activity in the mouse-forced swimming test as did the sigma(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 sigma(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 sigma(1) receptor agonist on these behavioral responses, and an interaction of the drug with the sigma(1) receptor must be considered in its pharmacological actions.

Taken together with the many other research papers and preclinical murine studies showing the therapeutic promise of Sigma-1 receptor agonism, it seem Anavex are the first to focus on Sigma-1 agonism in humans together with muscarenic M1 modulation, which appears to trigger multiple and interacting forms of synaptic plasticity.

Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice

We will see how the market reacts as we near readouts and of course it will be intriguing to say the least what results the readouts may bring.