Post On “Multi-Targeted Ligands (MTDLs) Binding the SIGMAR1 Receptor as Promising Therapeutics” $AVXL Blarcamesine Anavex3-71

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The paper of the same title, link here , described number of compounds and their chemistry, among them it mentioned ANAVEX 2-73 and 3-71 as examples of the most studied drugs in the class of MTDLs drugs. It also listed number of other drugs and their targets besides SIGMAR1, touching here on the logic of pain-relief and fighthing cancers which might be connected with the functioning of the Brain Blood Barrier.

There are two types MTDL drugs. Hybrid Drugs which are synthesized from two drugs with “weak bonds” between them to be easly metabolized by the liver producing two metabolites acting on two different receptors. The other type is Chimeric Drugs which are combination of two or more acting domains with strong bonds, acting on two or more receptors. They have better pharmcokinetics and better interaction with the targets.

The paper describes trials at synthesis of such drugs, all working on SIGMAR1 and on other receptors. What is very interesting is that in Mitochondria Associated Membranes where SIGMAR1 protein most likely resides the protein itself occures in oligomer structure. This has very interesting consequences as agonist and antagonist are not clearly defined by binary like action. Agonists tend to lower the number of copies of the protein in these structures more than the antagonists, in very gradual manner from drug to drug. This creates a situation where different agonist and antagonist can have varying therapeutics effect based on the minutia of their chemistry. The therapeutic effect can be dependent on the chemical structure of the drug and be very specific to the drug itself. Quote:

…..the different oligo‐ meric structures could be responsible for the many activities performed by these versatile receptors, with agonists and antagonists differently influencing the association among protomers: agonists produce lower oligomeric structures such as monomers and dimers, while antagonists produce higher ones [29].

There is plethora of very specific to chemistry information, of SIGMAR1 and drug design in this paper.

I want to quote the paper on the location of the SIGMAR1 receptor in human body. This is very interesting as number of organs might be ultimately under the beneficial influence of the SIGMAR1 drugs. Yet, I have to add that these can be either beneficial or harmful.

σ1 Receptors have been found in the central nervous system (CNS), particularly in the granular layer of the olfactory bulb, in many cortical layers, and in the dentate gyrus [6], where they exert their most important activities. A slightly lower expression has been also found in some pyramidal layers of the hippocampus, various hypothalamic nuclei, the septum, the central gray, the motor nuclei of the hindbrain, and the dorsal horn of the spinal cord [6]. At the cellular level, σ1 receptors have been found in ependymocytes, which border the ventricular compartments, and in neurons located within the CNS parenchyma [6].

In peripheral organs, σ1 receptors have been found in the gastrointestinal tract [7], vas deferens [8], in liver and kidney [9], heart [10], adrenal medulla, pituitary, testis, and ovaries [11].

The olfactory bulb referece to the sense of smell. Haven’t we all heard about the peanut butter smell test for Alzheimer’s?

Another quote from the paper.

The neuroprotective action of σ1 receptor agonists is well established, and it has been proved that this activity is exerted through different mechanisms such as intracellular Ca2+ regulation, the prevention of oxidative stress, and anti‐apoptotic effects. The σ1 subtype contributes to protein homeostasis: it can stimulate neurotrophin receptor signaling and reduce protein aggregation responsible for neurodegenerative disease, and it can also ac‐ tivate autophagy as a protective mechanism against damage arisen by misfolded proteins. Recently, many studies proved the ability of σ1 receptors to directly or indirectly interact with receptors or enzymes with key roles in neurodegeneration, particularly in Alz‐ heimer’s disease (AD). Importantly, in patients with AD, a reduction of σ1 receptor density [20] has been demonstrated. Some studies attributed such reduction to the E4 variant of the apolipoprotein E gene (APOE 4) [21], although some controversies still exist [22]. All these mechanisms can promote cell survival and consolidate the role of the σ1 receptor as a target for therapies against neurodegeneration [23].

The key piece of information is that Alzheimer’s patients display reduction in SIGMAR1 incidence in CNS cells. Agonist such as Blarcamesine could stimulate release of the beneficial proteins from the MAM domains to compensate for the lower incidence on SIGMAR1 protein. The other piece of infomation is tentatively connecting this with the APOE e4 gene variant. I have “committed” a post where I stated that APOE e4 carriers were helped by Blarcamesine but I assumed that those 3 which I dentified were drop outs, but they were actually helped and stayed in the trial. We have anecdotal evidence from later data on the 3 year performance of the High Concentration Cohort, keeping 8 out of 9 in the cohort over 3 years time, and Dr. Missling saying that (praphrase) even those with bad genetics can be helped if dosed long enough.

In this particular study in late-onset Alzheimer’s (LOAD) , about 56% are APOE e4 carriers. Those with two copies of e4 are almost 14 times more likely to get AD than the general population. Those with one copy, like e3e4, are 2.33 times more likely. Compare this with 75% carriers in the High Concentration Cohort.

If I am not wrong APOE e4 is the only clear link in genetics to Late-Onset Alzheimer’s Disease. If this connection between APOE e4 and SIGMAR1 is indeed true then there is a clear connection between SIGMAR1 lower incidence and Alzheimer’s. Since the SIGMAR1 covers broad spectrum of physiology, this could be overwhelming evidence that SIGMAR1 agonist and among them Blarcamesine and Anavex3-71 are the Alzheimer’s go to drugs, and not only Alzheimer’s. Most other drugs usually interact with one or few of the compounds SIGMAR1 agonists release.

One of interesting facts, yet of little value for us, is that one of the endogenous ligands to SIGMAR1 is DMT which is a hallucinogen. YouTube is rife with stories of trips taken under the drug. One more quote on the various effects ligands to SIGMAR1 might cause:

Molecular dynamic simulations at the σ1 receptor binding pocket have shown how the diverse chemical structures to which high‐affinity σ1 receptor ligands belong may easily be accommodated producing different associations among pro‐ tomers that lead to the different activities observed.

The therapeutic search for various SIGMAR1 drugs has just started. Number of drugs which had been previously treating other disease have now been connected with SIGMAR1 interactions. A new wave of drugs are synthesized to have the ability to interact with SIGMAR1 and other receptors. Not all of them are going into the clinic but the capabilities of SIGMAR1 are now more than ever recognized as primary therapeutic target.

Both Blarcamesine and ANVEX3-71 are examples of MTDLs as they interact with SIRMAR1 and muscarinic receptors. ANAVEX3-71 has also been known to reduce beta-secretase 1 levels. This might be helpful in treating Lewy Bodies Dementia. Let me again quoote from the paper:

The effect of σ1 receptors in inflammation through microglia modulation has been reported [54,86,87], and AF710B was shown to reduce reactive astrocytes and activated microglia in the animals, as detected by the low levels of glial fibrillary acidic protein (GFAP) and ionized calcium‐binding adapter molecule 1 (Iba‐1). Notably, astrocytes and microglia are increased in number and size in AD patients.

In addition to AF710B and ANAVEX 2‐73, Anavex Life Sciences Corp portfolio com‐ prehends an isomer of ANAVEX 2‐73, named ANAVEX 1‐41 (Figure 2) that next to the activity toward σ1 and M1 receptors, also displays activity for α1, 5‐HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (!/pipeline).

I have presented here information mostly pertaining to Alzheimer’s and neurodegenerative diseases. SIGMAR1 is also through the method of MTDLs implicated in creation of new drugs fighting pain and drug resistant cancer cells. Next post will be drawing on that theme from the same paper.


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