Blarcamesine

Blarcamesine acts primarily as an agonist of the sigma σ₁ receptor (affinity (IC₅₀ Tooltip half-maximal inhibitory concentration) = 860nM).^[2] To a lesser extent, it is also an agonist of the muscarinic acetylcholine M₁ receptor (affinity = 5μM) and of the ionotropic glutamate NMDA receptor (affinity = 8μM).^[2]

Blarcamesine was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.^[3] 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.^[3] Experiments in mice have found that M₁ and M₃ receptor agonists inhibit the formation of β-amyloid 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 β-amyloid 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 β-amyloid accumulation.^[5]

σ₁ receptor 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.^[3] The σ₁ 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 σ₁ receptor agonists stimulate the anti-apoptotic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.^[6] Results from Maurice (2016) found that σ₁ receptor agonists may offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or memantine, a NMDA receptor antagonist.^[7]

In December 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended the refusal of a marketing authorization for Blarcamesine Anavex, a medicine intended for the treatment of Alzheimer's disease.^[13] The applicant for this medicinal product is Anavex Germany GmbH.^[13] A request was made by the applicant for the committee to re-examine its opinion.^[13]