Anavex Life Sciences Corp (AVXL)

[MycroftHolmes]

RE: 273 distinctions

Apologies for the length of my reply. It seemed good to leave this as one complete response.

I recommend that one read the very complete Nobel Analysis before delving into any academic papers.
http://nobleresearch.com/reports/AVXL_20170206_9669.pdf

I tend to break down the research into 2 categories:
1) What is the problem we are trying to solve?
2) Is A2-73 promising amongst sigma receptors to solve these problems?

1) What is the problem we are trying to solve?
One can look at the causes of neurodegeneration mentioned in the excellent paper you cited
(http://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tuccop_pubs )

Common mechanisms of neurodegeneration
- Excitotoxicity and calcium overload
- Oxidative and nitrosative stress
- Endoplasmic reticulum (ER) stress
- Mitochondrial dysfunction
- Reactive gliosis

2) Is A2-73 promising amongst SR1 active molecules to solve these problems?

Neuroprotective actions by sigma ligands
- Modulation of calcium homeostasis and glutamate activity
- Attenuation of reactive species production
- Modulation of ER and mitochondrial function
- Modulation of glial activity


General A2-73 Facts
A2-73 acts as an agonist at M1 and S1 receptors, acts as an antagonist to M2, M3, NMDA receptors, and at high enough doses as an antagonist to sodium and calcium channels. The compound appears to have influence on IRE1 and Bcl-2 which seems to impede apoptosis signaling thereby prolonging cell life and modifies ion channels at Mitochondria to assist in homeostasis. In general, the compound seems to lower oxidative stress, reduce mitochondrial dysfunction, prolong apoptosis and thus cell life, and reboot the cellular machinery to clear mis-folded proteins via the usual cell process.

When reading the science, I tend to keep this cheat sheet handy

A2-73 molecules are:
Sigma-1 receptor agonists;
Muscarinic M1 receptor agonists;
Muscarinic M2 receptor antagonists;
Muscarinic M3 receptor antagonists;
NMDA receptor antagonists;

Calcium channel antagonists;
Chloride channel modulators;
Sodium channel antagonists;
Sodium channel modulators


A2-73 has duration
Both the compound and its metabolite are active.

A2-73 is well tolerated/selective
The compound's is more selective to SR1 than other compounds which suggests a more targeted SR1 effect with reduced side-effects. Unlike other SR1 compounds (cocaine) A2-73 is reportedly only active in cells under stress. The exact mechanism here is unknown to me but I assume has to do with Ca+ ion imbalance.

While preclinical evidence suggests that sigma-1 receptor agonists may be useful in treating Alzheimer's disease, no selective sigma-1 agonist is currently available for clinical use. Two currently approved drugs, donepezil and memantine, both act on sigma-1 receptors in addition to their other primary pharmacological targets, but whether any of their therapeutic effects are mediated by sigma-1 receptor activity has not been determined.
http://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tuccop_pubs

A2-73 impacts modulation of calcium homeostasis and glutamate activity, Attenuation of reactive species production, Modulation of ER and mitochondrial function
Through a cascade of activity, SR1 agonists influence Ca+, ROS, and Apotosis signals both at the ER-Mitochondira MAM and at other parts of the cell. A2-73 also acts directly as a NMDA antagonist which is thought to further increase this SR1 effect; An important added punch.

Upon ER Ca2+ depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca2+ signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis.
http://www.cell.com/cell/abstract/S0092-8674(07)01099-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867407010999%3Fshowall%3Dtrue&cc=y=

Recent studies now suggest the possibility that s-1Rs could exert neuroprotective effects via targeted disruption of protein-protein interactions between NMDARs and their associated intracellular signaling machinery, specifically the neuronal nitric oxide synthase (nNOS). This targeted disruption of protein-protein interactions between NMDARs and nNOS results in lower levels of nitric oxide generation, thus having a neuroprotective effect.
http://www.karger.com/Article/Abstract/376549

A2-73 Postpones cell death and provokes Unfolded Protein Response
As proper SR1 agonist, it sets off a chain reaction to help the cell 'reboot' and recover its function.

A2-73 mixed s1/muscarinic ligand shows evidence of being neuroprotective in Alzheimer’s disease
As the original question had to do with what makes A2-73 'different' it is instructive to note that A2-73 outperformed PRE-084 another highly selective SR1 agonist.

The main objective of the present study was to establish whether the mixed s1/muscarinic ligand ANAVEX2-73, shown to be neuroprotective in Alzheimer’s disease (AD) models in vivo and currently in clinical phase I/IIa, could have the ability to reduce the appearance of hyperphosphorylated Tau and amyloid-ß1–42 (Aß1–42) in the Aß25–35 mouse model of AD. We therefore first confirmed that Aß25–35 injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3ß (GSK-3ß) in the mouse hippocampus. Second, we showed that the kinase activation, and resulting Tau alteration, directly contributed to the amyloid toxicity, as co-administration of the selective GSK-3ß inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and Aß25–35-induced memory impairments. Third, we analyzed the ANAVEX2-73 effect on Tau phosphorylation and activation of the related kinase pathways (Akt and GSK-3ß). And fourth, we also addressed the impact of the drug on Aß25–35-induced Aß1–42 seeding and observed that the compound significantly blocked the increase in Aß1–42 and C99 levels in the hippocampus, suggesting that it may alleviate amyloid load in AD models. The comparison with PRE-084, a selective and reference s1 receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and s1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.
http://www.nature.com/npp/journal/v38/n9/full/npp201370a.html

Just my 2 cents. Hope others performing due diligence on the science behind A2-73 find this helpful.

Cheers

Mycroft.