Blarcamesine (developmental code name ANAVEX 2-73) is an experimental drug which is under development for the treatment of Alzheimer's disease and a variety of other indications.[1]
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 trials for Alzheimer's disease, Anavex Life Sciences reported that in patients with a fully functional SIGMAR1gene, which encodes the σ1 receptor targeted by blarcamesine, the drug improved cognition as measured by the mini-mental state examination (MMSE) by 14% after 70weeks 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 14weeks of treatment.[8]
The synthesis of Blarcamesine is via the following method:[10][11][12] (Precursor:[13][14])
The reaction between benzophenone [119-61-9] and succinic anhydride [108-30-5] in the presence of zinc chloride give 2,2-Diphenyloxolane-3-carboxylic acid, PC151808451 (1). The halogenation of with thionyl chloride (2) followed by dimethylamine gives the amide and hence N,N-dimethyl-5-oxo-2,2-diphenyloxolane-3-carboxamide, PC15187451 (3). Strong reduction with lithium aluminium hydride both removes the amide carbonyl as well as reduces the butyrophenone moiety giving a diol and hence 2-[(dimethylamino)methyl]-1,1-diphenylbutane-1,4-diol, PC15187448 (4). Acid catalyzed ring closure completed the synthesis of Blarcamesine (5).
^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. PMID26386305. S2CID40336723.
