ANAVEX2-73 is derived from aminotetrahydrofuran. This drug is in Phase II trials for Alzheimer's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson's disease, Rett syndrome, stroke. ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist. ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.
This drug has ki values lower than 500 nM for all M1–M4 subtypes demonstrating that it acts as a powerful muscarinic compound. ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment. M1 receptor agonists are known to reverse the amnesia caused by scopolamine. Scopolamine is used in the treatment of Parkinsons Disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach. This is done by a direct competitive interaction. Muscarinic receptors are involved in both the short term and long term memories. Researchers in mice have found that M1 and M3 receptor agonists have shown to inhibit formation of amyloid-beta, and to target GSK-3B. Furthermore, M1 receptor activates AF267B, which in turn blocks B-secretase which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaque. This enzyme is involved in the formation of Tau plaques common in Alzheimer disease, so therefore M1 receptor activation decreases tau hyperphosphorylation and amyloid-beta accumulation.
Sigma1 activation appears to be only involved in long-term memory processes. This explains partly why ANAVEX2-73 seems to be more effective in reversing long-term memory problems caused by scopolamine compared to short-term memory deficits. Sigma 1 receptor is on the mitochondria-associated endoplasmic reticulum membranes and acts as a modulator the ER stress responses and local calcium exchanges with the mitochondria. This compound prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity. This drug appears to be an important target in Alzheimer's disease to protect against mitochondrial damage. ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibit anti-apoptotic and anti-oxidant activity. This is due in part because sigma1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB. Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.