Anavex Life Sciences Corp (AVXL)

[sokol]

UniProtKB/Swiss-Prot Summary for SIGMAR1 Gene

....Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria.....

https://www.genecards.org/cgi-bin/carddisp.pl?gene=SIGMAR1

But, AVXL 2-73 is a mixed ligand for sigma1/muscarinic receptors. Doc's concern is this: "M4 agonism may worsen tremor (see link below where I discussed in more detail). Clinically, muscarinic antagonists help motor function in PD so agonists would not be expected to help. However, there is potential for the dementia to improve with A273 in PDD via M1 agonism (and maybe S1R), similar to possibility in AD.
An ideal medication for PDD may be an M1 agonist and M4 antagonists.".

However, see this:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286317/

Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease

Abstract

Antagonists of the muscarinic acetylcholine receptors (mAChRs) were among the first treatments for Parkinson's disease. ...Understanding the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to the development of novel agents that have antiparkinsonian activity with fewer adverse effects. .... ...M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in nonselective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased haloperidol-induced catalepsy in rats but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.

2. https://www.michaeljfox.org/grant/highly-selective-m1-muscarinic-receptor-positive-allosteric-modulators-treatment-parkinsons

Hypothesis:
We believe that small molecules that affect the function of the M1 mAChR in a highly selective manner have the potential to deliver novel, well-tolerated and efficacious drugs to treat learning and memory deficits in individuals with PDD.

Study Design:
We have generated small molecules of novel chemical classes that are positive allosteric modulators of the M1 mAChR and have a good understanding of the structure-activity relationship of these molecules. Based on this knowledge, we will synthesize these molecules and optimize them for target engagement in the brain and safety.