Blarcamesine

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 acts as an agonist of the sigma σ₁ receptor, the muscarinic acetylcholine M₁ receptor, and the ionotropic glutamate NMDA receptor.^{[2] [1]}

The drug was developed by Anavex Life Sciences.^[1] As of August 2024, it is in preregistration for Alzheimer's disease, phase 2/3 clinical trials for fragile X syndrome and Rett syndrome, phase 2 trials for Parkinson's disease, and phase 1 trials for Angelman syndrome and infantile spasms.^[1] It was also under development for the treatment of amyotrophic lateral sclerosis (ALS), anxiety disorders, autistic spectrum disorders, cognition disorders, multiple sclerosis, and stroke, but development for these indications was discontinued.^[1]

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

Blarcamesine may function as a prodrug for ANAVEX 19-144 ^[2] as well as act as a drug itself. ANAVEX19-144 is a positional isomer of ANAVEX 1-41, which is similar to blarcamesine but is not as selective for sigma σ₁ receptor.^[1]

In trials for Alzheimer's disease, Anavex Life Sciences reported that in patients with a fully functional SIGMAR1 gene, which encodes the σ₁ receptor targeted by blarcamesine, the drug improved cognition as measured by the mini-mental state examination (MMSE) 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.^[8]

A related drug is ANAVEX 3-71.^{[2] [9]}

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).