Blarcamesine

Last updated

Blarcamesine
ANAVEX2-73.svg
Clinical data
Other namesANAVEX 2-73
ATC code
Identifiers
  • 1-(2,2-Diphenyltetrahydro-3-furanyl)-N,N-dimethylmethanamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H23NO
Molar mass 281.399 g·mol−1
3D model (JSmol)
  • O3C(c1ccccc1)(c2ccccc2)C(CN(C)C)CC3
  • InChI=1S/C19H23NO/c1-20(2)15-18-13-14-21-19(18,16-9-5-3-6-10-16)17-11-7-4-8-12-17/h3-12,18H,13-15H2,1-2H3
  • Key:BOTHKNZTGGXFEQ-UHFFFAOYSA-N

Blarcamesine (developmental code name ANAVEX 2-73) is an experimental drug which is under development for the treatment of Alzheimer's disease and other indications. [1]

Contents

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]

Pharmacology

Pharmacodynamics

Blarcamesine 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]

Synthesis

The synthesis of blarcamesine is via the following method: [8] [9] [10] (Precursor: [11] [12] )

Blarcamesine synthesis.svg

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).

Society and culture

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]

Research

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. [14]

References

  1. 1 2 3 4 5 "Anavex Life Sciences". AdisInsight. 1 August 2024. Retrieved 12 September 2024.
  2. 1 2 3 Malar DS, Thitilertdecha P, Ruckvongacheep KS, Brimson S, Tencomnao T, Brimson JM (May 2023). "Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders". CNS Drugs. 37 (5): 399–440. doi:10.1007/s40263-023-01007-6. PMC   10173947 . PMID   37166702.
  3. 1 2 3 "Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma" (PDF). Journal of Psychopharmacology . Archived from the original (PDF) on 12 November 2015. Retrieved 25 May 2016.
  4. 1 2 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.
  5. 1 2 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.{{cite journal}}: CS1 maint: overridden setting (link)
  6. ↑ Lahmy V, Long R, Morin D, Villard V, Maurice T (28 September 2015). "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.
  7. ↑ 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. S2CID   40336723.
  8. ↑ Alexandre Vamvakides, et al. WO1997030983
  9. ↑ Alexandre Vamvakides, FR2897535 (2007).
  10. ↑ Αλεξανδρος Βαμβακιδης, GR1004208 (2003)
  11. ↑ Jan Benes & Jiri Krepelka, CS217732 (1983).
  12. ↑ [Justus Liebigs. Ann. Chem. 526, 1 (1936)]
  13. 1 2 3 "Blarcamesine Anavex EPAR". European Medicines Agency (EMA). 12 December 2025. Retrieved 22 December 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. ↑ "Anavex Life Sciences Reports ANAVEX®2-73 (blarcamesine) featured as a Disease-Modifying Small Molecule in Phase 3 Clinical Trials in a New Publication in Medical Journal titled "Future Avenues for Alzheimer's Disease Detection and Therapy"" (Press release). Anavex Life Sciences. 16 March 2021. Retrieved 22 December 2025– via GlobeNewswire News Room.
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