Anavex not only has Blarcamesine (Anavex 2-73) but also has Anavex 3-71 which could be orders of magnitude more effective than another drug for the treatment of Alzheimer's disease and other CNS diseases and/or conditions.
Do you know what orders of magnitude means 10X is one order of magnitude increase 100X is two orders of magnitude increase 1,000X is 3 orders of magnitude increase 10,000X is 4 orders of magnitude increase orders of magnitude is plural meaning more than 1
Anavex 3-71 (formerly known as AF710B) is orders of magnitude more potent than donepezil (Aricept)and other agonists acting either on the M1 or the s-1 receptors, respectively,” Fisher said.
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First, s-1 receptors. They are strangers to published AD drug development, though pharmaceutical industry research on compounds active in the CNS comes across them frequently. First identified in the 1970s, these receptors were studied pharmacologically until Austrian researchers cloned the gene (Hanner et al., 1996). In the years after, scientists learned that many endogenous peptides, for example, pregnanolone and neuropeptide Y, interact with these receptors, and subsequent knockout and other biological studies showed they act as chaperones associated with the endoplasmic reticulum (Hayashi and Su, 2007). Unusually for chaperones, a slew of endogenous ligands that act as agonists or antagonists operate the s-1 receptor, Tangui Maurice at INSERM in Montpellier, France, told the audience in Zuers.
The s-1 receptor’s role in neurodegenerative diseases is poorly understood. One mutation appears to cause juvenile ALS (Al-Saif et al., 2011), but beyond that, data on its genetic contribution remain sparse (see AlzGene listing).
The receptor is ubiquitous. Besides neurons, astrocytes, oligodendrocytes, and Schwann cells, the liver, spleen, heart, kidney, intestine, and other organs express it. It is a transmembrane protein that lives in the ER, particularly at touch points with mitochondria. There, it modulates calcium and influences the composition of lipid rafts. The receptor becomes active in response to ligand binding and in conditions of ER stress. It protects mitochondria by influencing production of radical oxygen species and expression of the anti-apoptotic gene BCL2. It also sits in the plasma membrane, where it interacts with receptors ranging from TrkB, the muscarinic acetylcholine receptor, to sodium and potassium channels. “The s-1 receptor is an important activity-dependent signaling modulator of multiple intracellular pathways in the cell,” Maurice told the audience in Zuers.
How can the s-1 receptor influence myriad functions in cells? It does so by way of cooperating with other receptors. At least in some cases, it forms heteromers with them, said Abraham Fisher, Israel Institute for Biological Research, Ness-Ziona (e.g., see Navarro et al., 2010). This constellation is how the s-1 receptor may work as a target for certain drugs. For example, haloperidol treats schizophrenia by acting on the dopamine D2 and s-1 receptors; fluoxetine treats depression through a combined effect on the serotonin and s-1 receptors, and donepezil treats AD through an effect on a cholinesterase and the s-1 receptor.
In Zuers, both Fisher and Maurice presented their respective efforts at finding small molecules that tickle this receptor in a way that might treat AD better than current drugs do. Fisher introduced AF710B, a bicyclic heterocyclic spiro-compound that he said selectively activates both the muscarinic M1 receptor and the s-1 receptor. In detailing its effects on a list of phenotypic parameters—it increases sAPPa secretion, decreases tau hyperphosphorylation and GSK-3ß activity, decreases Bax, and increases BCL2 expression in mitochondria—Fisher emphasized that the former two effects come through the M1 receptor and the latter two through the s-1 receptor. Unlike previous compounds Fisher developed, which were mainly M1-selective orthosteric agonists, AF710B is an allosteric M1 receptor agonist. Its heteromer-specific effects differentiate it from other M1 agonists and modulators. Fisher claimed that the new compound is exquisitely potent, acting as a cognitive enhancer in rats at 1 to 30 micrograms (not milligrams) per kilogram body weight. According to Fisher, the compound is orally available with a safety margin of more than 50,000 times the minimally active dose. “Those are orders of magnitude more potent than donepezil and other agonists acting either on the M1 or the s-1 receptors, respectively,” Fisher said.
Fisher proposed that the compound has a unique mechanism of action, whereby it sensitizes the M1 receptor through heterodimerization with the s-1 receptor in the membrane of the ER, adding, however, that heteromerization of these receptors has not been formally proven. “We are looking to license it for drug development,” Fisher said.
“One microgram (µg) is one millionth of a gram. At this dosage, a 150lb human (weighing 68 kg) with Alzheimer's would take 680 µg, 0.68 milligrams, each day. Less than a single milligram. By any measure, that’s very fractional compared to the many milligram doses of Anavex 2-73 (blarcamesine) being used in human clinical trials”.
So is that why Anavex used the magnitudes higher doses in the range of 5mg - 200mg in the human P1 trial of A3-71?
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