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Other names | ANAVEX2-73 |
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Formula | C19H23NO |
Molar mass | 281.399 g·mol−1 |
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Blarcamesine (development code ANAVEX2-73) is an experimental drug developed by Anavex Life Sciences.
It is in phase IIb/phase III trials for Alzheimer's disease and Rett syndrome, phase IIa trials for Parkinson's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis and stroke.[1][2] Blarcamesine acts as a agonist at the human SIGMAR1 and CHRM1 receptors.[1]
In trials for Alzheimer's disease, Anavex Life Sciences reported that in patients with a fully functional SIGMAR1 gene, which encodes the sigma-1 receptor targeted by blarcamesine, the drug improved cognition as measured by the mini-mental state examination by 14% after 70 weeks of treatment. Competence in activities of daily living was improved by 8% in the same subgroup of patients. Additionally, in trials for Parkinson's disease, episodic memory was significantly improved after 14 weeks of treatment.[3]
Blarcamesine may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is a positional isomer of ANAVEX 1-41, which is similar to blarcamesine but it is not as selective for sigma receptor.[2]
Blarcamesine 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.[4] 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.[4] This is via competitive inhibition of muscarinic receptors.[4] 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.[clarification needed] 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[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer's disease.[clarification needed][5] Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[5]
Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why blarcamesine 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. Blarcamesine 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.[clarification needed] Blarcamesine inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. Blarcamesine 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.[6] Results from Maurice (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.[7]