Here are a few items (5 total) from the past that I believe may set AVXL 2-73 apart from other receptor agonist discussed on this board.
''Anavex 2-73 reportedly binds the sigma-1 receptor in the high nanomolar and the muscarinic receptor in the low micromolar range.'' SEE # 1 BELOW.
"Preclinical Data of ANAVEX 1-41 and ANAVEX 2-73, Show Highly Potent Anti-Amnesic and Neuroprotective Activity Against Amyloid Beta (25-35) Peptide Toxicity in Alzheimer's Disease (AD) Animal Mode." # 2 BELOW.
"ANAVEX2-73 is metabolized into the pharmacologically active metabolite, ANAVEX 19-144. The apparent elimination half-life of the metabolite (21.45hr) is approximately twice that of ANAVEX2-73 (10.71 hr) hence the active metabolite result in extended activation of the sigma-1 receptor." #3 BELOW.
An extended half-life implies an increased impact on patients.
"Preclinical data reveals that ANAVEX 2-73 and ANAVEX 19-144 exhibit significant anti-amnesic, neuroprotective and anticonvulsant properties in a variety of in vitro systems and specialized animal models. These activities involve sigma-1, muscarinic and NMDA receptors as well as ion channels, indicating a unique mode of action. In AD animal models, ANAVEX 2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic, anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to sigma-1 receptors and moderate affinities to M1-4 type muscarinic receptors. ANAVEX 2-73 has shown a potential dual mechanism which may impact both amyloid and tau pathology. ANAVEX 19-144 controls seizures and the epileptogenesis process in animal models. Moreover, its neuroprotective properties may prevent the process that causes long-term damage to tissue and cells as well as biochemical and physiological alterations to the brain from epileptic seizures." (10 K Part 1, ITEM 1. BUSINESS). #4
Orevko post (# 5 below) discussed patent rights on this board in the past and says this about AVXL 2-73 and 19-144: "I read through that new application last week and it's quite interesting. It gives some additional insight into the inner workings of Anavex 2-73 and Anavex PLUS. The metabolite (Anavex 19-144) really seems to be the secret sauce. ". Many excellent posts from the past by Orevko may be located on this board, and the patent Orveko refers to is something I or we all may review to learn more about the inner workings of Anavex’s drugs.
1. Chemical Name: Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride Therapy Type: Small Molecule (timeline) Target Type: Other (timeline) Condition(s): Alzheimer's Disease U.S. FDA Status: Alzheimer's Disease (Phase 2) Company: Anavex Life Science Corp. BACKGROUND This compound is an agonist of the intracellular sigma-1 chaperone protein. Specifically, it is a mixed ligand for sigma1/muscarinic receptors. Expressed in most tissues and located at focal contacts between mitochondria and the endoplasmic reticulum, the sigma-1 receptor forms heterodimers with many other membrane receptors, and as such influences multiple cellular pathways and physiological processes. Anavex 2-73 reportedly binds the sigma-1 receptor in the high nanomolar and the muscarinic receptor in the low micromolar range.
The compound has been reported to have memory-preserving and neuroprotective effects in mice treated with the muscarinic receptor antagonist scopolamine, with synthetic Aß oligomer injection, or with the NMDA receptor agonist dizocilpine (Villard et al., 2011). A recent study suggested that Anavex 2-73 may block tau hyperphosphorylation (see Jan 2013 conference news and Lahmy et al., 2013).
2. Preclinical Data of ANAVEX 1-41 and ANAVEX 2-73, Show Highly Potent Anti-Amnesic and Neuroprotective Activity Against Amyloid Beta (25-35) Peptide Toxicity in Alzheimer's Disease (AD) Animal Mode
3. ANAVEX2-73 is metabolized into the pharmacologically active metabolite, ANAVEX 19-144. The apparent elimination half-life of the metabolite (21.45hr) is approximately twice that of ANAVEX2-73 (10.71 hr) hence the active metabolite result in extended activation of the sigma-1 receptor.
4. "Preclinical data reveals that ANAVEX 2-73 and ANAVEX 19-144 exhibit significant anti-amnesic, neuroprotective and anticonvulsant properties in a variety of in vitro systems and specialized animal models. These activities involve sigma-1, muscarinic and NMDA receptors as well as ion channels, indicating a unique mode of action. In AD animal models, ANAVEX 2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic, anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to sigma-1 receptors and moderate affinities to M1-4 type muscarinic receptors. ANAVEX 2-73 has shown a potential dual mechanism which may impact both amyloid and tau pathology. ANAVEX 19-144 controls seizures and the epileptogenesis process in animal models. Moreover, its neuroprotective properties may prevent the process that causes long-term damage to tissue and cells as well as biochemical and physiological alterations to the brain from epileptic seizures." (10 K Part 1, ITEM 1. BUSINESS)
5. Orveko I-Hub post -Wednesday, 01/27/16 01:06:47 AM Re: seventhwave post# 51618 0 Post # of 176791 Anavex 19-144 is the active metabolite of Anavex 2-73, i.e., when you ingest A2-73, your body metabolizes it into A19-144. A2-73 is therefore itself a drug and also a pro-drug for A19-144. One-two punch.
Dr. Vamvakides signed over Greek patent rights for A2-73 (AE 37), A19-144 (AE 37 MET), and other compounds per the following contract (effective January 29, 2007) - scroll down to the very end (Schedule A):
Most of the U.S. patent applications related to the original Greek patents are still pending, but all are either directly assigned to Anavex or are otherwise contractually owned by Anavex. I specifically asked IR about this new application and they say it is "contractually the property of Anavex."
Even though this new application (14/865862) was just published, it's priority date is March 28, 2013, same as 13/940352 and 14/395581. This is because they are all essentially "continuations" of the original Greek patent application GR2013000018 (WO2014155138). This Greek application (which is where Anavex PLUS comes from) was not part of the original contract with Vamvakides, but is still the contractual property of Anavex per the 2012 addendum to the original contract (effective January 11, 2013): Quote: 1.1 (e) Inventions made during the term of the CONTRACT filed on or after January 29, 2007 and not falling under 1.1 (a) - (d) wherein Dr. Vamvakides is an inventor.
Anyway, I read through that new application last week and it's quite interesting. It gives some additional insight into the inner workings of Anavex 2-73 and Anavex PLUS. The metabolite (Anavex 19-144) really seems to be the secret sauce.
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