ANAVEX2-73

ANAVEX2-73 is an experimental 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.[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.[1] 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.[2]

ANAVEX2-73
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H23NO
Molar mass281.399 g·mol−1
3D model (JSmol)

Properties and uses

ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[3] Scopolamine is used in the treatment of Parkinson's disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[3] This is via competitive inhibition of muscarinic receptors.[3] Muscarinic receptors are involved in the formation of both short term and long term memories.[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B. Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme is involved in the formation of Tau plaques, which are common in Alzheimer's disease.[4] Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[4]

Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 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. 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 exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.[5] 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.[6]

References
  1. "Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma" (PDF). Journal of Psychopharmacology. Archived from the original (PDF) on 2015-11-12. Retrieved 2016-05-25.
  2. "ANAVEX 2-73". Adis Insight. Springer Nature Switzerland AG. Retrieved 2016-05-25.
  3. Malviya M, Kumar YC, Asha D, Chandra JN, Subhash MN, Rangappa KS (August 2008). "Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models". Bioorganic & Medicinal Chemistry. 16 (15): 7095–101. doi:10.1016/j.bmc.2008.06.053. PMID 18640043.
  4. Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlström H, et al. (September 2016). "Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production". Journal of Cellular and Molecular Medicine. 20 (9): 1686–95. doi:10.1111/jcmm.12863. PMC 4988279. PMID 27203684.
  5. Lahmy V, Long R, Morin D, Villard V, Maurice T (2015-09-28). "Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model". Frontiers in Cellular Neuroscience. 8: 463. doi:10.3389/fncel.2014.00463. PMC 4299448. PMID 25653589.
  6. Maurice T (January 2016). "Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments". Behavioural Brain Research. 296: 270–278. doi:10.1016/j.bbr.2015.09.020. PMID 26386305.
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