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Replies to post #208800 on Anavex Life Sciences Corp (AVXL)
09/08/19 12:04 AM
In this context a novel Sig-1R agonist, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), was developed. Pharmacologically, ANAVEX2-73 shows a dual activity on Sig-1 as well as on muscarinic receptors, acting with described affinities in the low micromolar range [26,27]. Previously, pre-clinical studies in animal models demonstrated robust disease-modifying activities of ANAVEX2-73. Regarding AD, ANAVEX2-73 has undergone testing in Phase 2a trial of patients demonstrating a favorable safety profile and a concentration-dependent improvement against exploratory endpoints [28,29,30]. A variety of neuromodulatory and neuroprotective effects are also already known for ANAVEX2-73, including mitochondrial protection in mouse models of AD, regulation of ERK activation and promotion of survival of astrocytes, as well as protection against oxidative stress [31,32,33].
First evidence for a possible link of Sig-1R, autophagy, and neurodegeneration has been recently shown in the context of ALS. It was discovered that ALS-linked mutant Sig1-R causes an accumulation of autophagic material and actually reduced autophagy [34], and that mice with genetically-altered Sig-1R show defective autophagy [35]. Moreover, it was demonstrated that cocaine-mediated autophagy in astrocytes involves Sig-1R [36]. In addition, it was found that a small-molecule Sig-1R modulator induces autophagic degradation of programmed-death ligand 1 (PD-L1) in cancer cells [37]. These findings prompted us to study the potential of ANAVEX2-73 to have an effect on autophagy in human HeLa and HEK293 cells (in vitro) as well as in C. elegans (in vivo), employing standard measures to analyze autophagic activity [38,39,40,41]. Moreover, the effects of ANAVEX2-73 on protein aggregation and, subsequently, the impact of protein aggregates on movement behavior in C. elegans were studied. Excitingly, ANAVEX2-73 is a potent inducer of autophagic flux in vitro and in vivo and ameliorates protein aggregate formation and paralysis in C. elegans.
