Anavex Life Sciences Corp (AVXL)

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re: "Is Donezepil affinity to s1R is stronger than other drugs which causes these drugs not able to attach to s1R leading to lower efficacy? "

That could be. Evidently, many different compounds can attach to it.

The lock and key receptor/ligand analogy might considered in the context of an experiance I had when a coworker and myself stepped outside one night for a smoke break. We noticed this guy going around to different cars tryng to unlock them. My friend decided to call plant security. I was about to kid him for being too paranoid, but then the fellow managed open one and I had a sudden realization. "Hey, wait a second. That's my car!" Perhaps it was due in part due to three cars being stolen out from under their noses a few nights before, but security was remarkably quick getting out there. Long story short, turns out he wasn't a car thief after all. A lot of cars do look alike. Sometimes the wrong key will still work in a lock it wasn't made for.

There are a lot of receptors dedicated to sensory input, notably, the sense of smell. The ability to sniff out food is an evolutionary advantage pretty much all creatures have adopted over the eons. In our modern age, *80,000 different chemicals have been added to the potential menu over the last 100 years. It turns out that cyanide, an extremely poisonous industrial chemical, smells just like almonds. It's the wrong molecular key, but due to pure chance, it still fits into the almond smell receptor, even though its chemical properties are radically different, to say the least.

( * "The Human Experiment" documentary video)

Donepizel was developed to inhibit the enzyme, acetylcholinerase, from performing its normal regulatory function of breaking down acetylcholine. Acetylcholine works as a neuromodulator in the brain and as a neurotransmitter elsewhere. It appears to be pure chance that donepizel also has a chemical affinity to several receptors. In the case of M2 amd M3, undesirable, but donepizel is applied as a therapy anyway.

S1 (Sigma-1) is beneficial but "An endogenous ligand for the s1 (S1) receptor has yet to be conclusively identified" . Which means that what activates it naturally "isn't completely understood" (another phrase one comes across frequently in CNS research literature).

https://en.wikipedia.org/wiki/Sigma-1_receptor

Another interesting thing about these receptors is that they are depicted as a circle of corkscrew molecules that serve as a kind of security system for a pore in the middle. When they encounter a molecule that they recognize, the pore will dialate open, which allows molecules to be sucked in to proceed along the labyrinth of passageways inside the cell to affect cell function e.g. protein dynamics.

Just like artficial sweeteners have no nutritional value, it's possible that donepizel, among the many different compounds of known affinity, may not exactly be what the S1 receptor needs, compared to 2-73, which was actually developed for receptor therapy.

"Maybe monotherapy is a better option in this case and dose optimization should be done with A2-73 only"

Agreed.