Anavex Life Sciences Corp (AVXL)

[makemydaze]

For the science buffs and anyone else including insomniacs here's a comprehensive article regarding the sigma-1. I highlighted the one sentence regarding 3-71.

The section regarding Anavex -

"Many pharmacological and genetic data have proven that activation of muscarinic M1 receptors (mAChRs) attenuates symptoms of neurodegenerative pathologies, as in the case of MTDLs able to bind both M1 and s1 receptors. The most investigated compound representative of this class is ANAVEX 2-73 (also known as Blarcamesine). This compound is in advanced clinical phases for several CNS diseases such as AD, Parkinson’s disease (PD), Rett, and Fragile X Syndromes (anavex.com/#!/pipeline, accessed Apr 3, 2021). In addition to binding M1 and s1 receptors, Blarcamesine also binds M2–M4 receptors (with micromolar affinity), Na+ channel site 2, and NMDA receptor (NMDAR). In this context, Fisher and co-workers, who previously developed orthosteric M1 receptors agonists (e.g., AF102B, AF267B, and AF292), extended their approach in order to target also s1 receptors. With this aim, compound AF710B (also known as ANAVEX 3-71, that can activate both M1 and s1 receptors with high potency and selectivity was identified. AF710B is a positive allosteric modulator (PAM) of M1 receptor, as it improves the efficacy of carbachol, and this activity, together with a comparable agonism at the s1 receptor can preserve synaptic elements in vitro. In vivo studies performed on trihexyphenidyl-treated rats and 3xTg-AD mice showed that AF710B can restore cognitive deficits and attenuate signs of AD phenotypes by the reduction of ß-secretase 1 (BACE1) levels, GSK3ß and CDK5/p25 activity (which contribute to the hyperphosphorylation of tau protein), neuroinflammation, soluble and insoluble Aß40 and Aß42 plaques, and tau pathology. In fact, AF710B reduces the expression of the putative BACE1, so that proteolytic fragments produced by ß-secretase were considerably lower in 3xTg-AD treated than in untreated mice. Moreover, tau kinases GSK3ß and CDK5 take part in the mechanism of hyperphosphorylation of tau protein. In particular, in AD patients, CDK5 activator p35 is cleaved to produce the protein p25, which binds with high affinity and activates GSK3ß. The activation of M1 receptors produces a reduction of GSK3ß expression, while the activation of s1 prevents the formation of CDK5/p25. Therefore, the inhibition of GSK3ß and CDK/p25 by AF710B, upon interaction with both M1 and s1 receptors, results as a promising approach in the treatment of tauopathies .

The effect of s1 receptors in inflammation through microglia modulation has been reported, 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.

Another study performed using AF710B on McGill-R-Thyl-APP transgenic (tg) rats revealed that this MTDL can reduce amyloid pathology and markers of neuroinflammation while increasing amyloid cerebrospinal fluid clearance and synaptic marker. The most important achievement is represented by the prolonged duration of these effects, which are maintained five weeks after the treatment is interrupted.

In addition to AF710B and ANAVEX 2-73, Anavex Life Sciences Corp portfolio comprehends an isomer of ANAVEX 2-73, named ANAVEX 1-41 (Figure 2) that next to the activity toward s1 and M1 receptors, also displays activity for a1, 5-HT2, and D3 receptors, with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline)."

https://www.mdpi.com/1422-0067/22/12/6359/htm