Replies to post #332445 on Anavex Life Sciences Corp (AVXL)

[DFRAI]

There is no peer review of a2-73

[Investor2014]

No mention of Anavex, but very interesting paper. Thank you for posting.

Here is the conclusions:

CONCLUSIONS
In the present work, we report on the design, synthesis, and
evaluation of novel bitopic sigma 1 modulators as valuable
pharmacological tools to investigate S1R oligomerization and
ligand recognition processes at the molecular level.
The series of S1R modulators herein described is based on
our in-house developed sigma 1 agonist (R)-RC-3350,65 and
comprises one acetamide derivative, seven homo-bitopic
derivatives characterized by different types of linkers, and
one hetero-bitopic ligand. The synthetic procedure to obtain
the target molecules has been successfully adapted and
optimized, affording the desired homochiral products in a
suitable amount and purity. The binding assays revealed that
compound 7 exhibits a high affinity toward the receptor,
comparable to that of monomeric model compound (R)-RC-
33. Notably, molecule 7 is considerably bulkier than the typical
S1R ligands, possibly the largest ligand endowed with low
nanomolar affinity identified so far. In silico studies showed that
7 is able to stabilize the open conformation of the receptor,
placing one pharmacophoric unit into the primary binding site
and the other giving favorable interactions with residues Q135
and H154 on the cytosol-exposed surface of the receptor. This
region seems to constitute a “recognition” binding site with
which S1R ligands may interact at first, before reaching the
occluded binding pocket identified by Schimdt in cocrystals.
45,46 This model is consistent with the one proposed for
metastable binding sites recently identified for other
proteins,3,25,28,29 and it could be exploited to develop novel
bitopic ligands with enhanced activity and/or selectivity
toward the S1R. Moreover, the results obtained may add a
piece to the complex puzzle of elusive S1R allosteric binding
sites: although some allosteric S1R modulators are known,
their binding sites have not been identified yet, nor the binding
dynamics of such compounds are fully characterized and
understood, but it is likely that activation of this site triggers a
conformational rearrangement that disrupts inactive high-order
oligomeric states of the S1R, favoring the biologically active
dimers and monomers.48,66
Finally, bitopic compound 7 was compared to monovalent
ligands 2 and (R)-RC-33 in a preliminary biological evaluation.
The tested compounds resulted in S1R agonists in the neurite
outgrowth assay,63 and 7 was as effective as the model
compound (R)-RC-33 in promoting cell differentiation even at
the lowest concentration tested (0.005 µM).

To the best of our knowledge, this represents the first report
on a bitopic sigma 1 ligand endowed with low nanomolar
affinity and agonist profile in a well-defined cellular model of
neuronal differentiation. Accordingly, our work paves the way
for the use of bitopic ligands as useful chemical tools for
deepening our understanding of the still enigmatic S1R and the
molecular mechanisms underpinning its important biological
functions.

I will leave further interpretation to Oh Say or some other poster with at least as thorough insights.