Replies to post #175832 on Anavex Life Sciences Corp (AVXL)

[bas2020]

What we can speculate, as to why 2-73 is a better S1R agonist, is what we've been told: that its metabolite is also an S1R agonist and that it's also an M1/M4 agonist. To which degree of either lends greater benefit is unknown to us. Have any other MOA aspects been revealed?

[jimmy_mcyoloswag]

My last 2 cents and then I‘m off to the holidays:

I would assume varying affinities / binding sites and activation levels of the receptor by the different compounds would change their effectiveness combatting symptoms as drugs.

Another factor would be cross-activation/inhibition of other impactful receptors.

Maybe unintended co-activation is needed/favorable, maybe pure and high affinity activation is key.

It would be interesting to compare the affinities of 2-73 and 3-71 to the SR1 and to other CNS receptors (like NMDA, GABAR etc..). My guess is 3-71 has a higher affinity and specificity for SR1.

In other terms: we‘re playing chords and need to find the note that causes the strongest resonance in our target glass.

Happy holidays y‘all!

[falconer66a]

Differing Molecular Architectures and Functions

...why A2-73 may give better results?

Apparently a number of molecules can have, incidentally, sigma-1 receptor agonist functions, including the Alzheimer’s drug donepezil (Aricept). Primarily, donepezil is an acetylcholinesterase inhibitor, which suppresses acetylcholinesterase, an enzyme that destroys acetylcholine, a nerve substance required for nerve impulse transmission. Preservation of acetylcholine by Aricept enhances normalized brain function. It therefore, in a moderate way, ameliorates the cognitive deficits of Alzheimer’s (but only for a period).

The molecular architecture of Anavex 2-73, however, very closely (perhaps exactly) matches the binding sites of the sigma-1 receptor proteins in the neuron. It makes a strong molecular connection, a binding fit, to the cellular structures and chemistries that control, chaperone, (among other things) calcium signaling between the endoplasmic reticulum and the mitochondrion.

In short, the sigma-1 receptor effects of Aricept are minor and incidental. For Anavex 2-73, they are direct and firm; because of its favorable (dare I say, unique) molecular architecture. A shriveled apple/sweet orange comparison.