Update on possible alternative targets of Anavex2-73

The pre-clinical study on FRX is impressive. At 1 mg/kg dose, Anavex2-73 fully restores the BDNF concentration to that of wild-type mouse. It also rescues most of the behavior and memory deficit. On the other hand, the study also shows that at 1 mg/kg, Anaxex2-73 does not displace high affinity S1R ligand to any detectible extent, which means it has minimal binding to S1R at 1 mg/kg in mice ( https://www.nature.com/articles/s41598-021-94079-7.pdf). Therefore, the effects most likely are the results of alternative targets. Then what is a possible alternative target?

FKBP12 inhibition induces the transcription and translation of BDNF (https://pubmed.ncbi.nlm.nih.gov/19393753/; https://molecularbrain.biomedcentral.com/articles/10.1186/1756-6606-2-33; ttps://europepmc.org/article/med/12706270). In the mouse FRX study, the biological effect at 1 mg/ml is most likely from FKBP12 inhibition!

The high dose human trial at 50 mg (assuming average patient at 75 kg) is technically equivalent to ~8 mg/kg in mouse. There should be some occupancy of S1R by 2-73 in human studies.

The restoration of BDNF concentration is a critical and unbiased biomarker. There are extensive reports to support the connection of BDNF loss with Alzheimer disease (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358753/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128436/ ).