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Blarcamesine

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Blarcamesine
Clinical data
Other namesANAVEX 2-73
ATC code
  • None
Legal status
Legal status
  • Investigational
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
FormulaC19H23NO
Molar mass281.399 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 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]

Pharmacology

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Pharmacodynamics

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Blacarmesine acts primarily as an agonist of the sigma σ1 receptor (affinity (IC50Tooltip 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]

Pharmacokinetics

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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]

Research

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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]

Other drugs

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

Synthesis

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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).

References

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  1. ^ a b c d e f "Anavex Life Sciences". AdisInsight. 1 August 2024. Retrieved 12 September 2024.
  2. ^ a b c d e 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. ^ a b c "Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma" (PDF). Journal of Psychopharmacology. Archived from the original (PDF) on 2015-11-12. Retrieved 2016-05-25.
  4. ^ a b c 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. ^ a b 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.
  6. ^ Lahmy V, Long R, Morin D, Villard V, Maurice T (2015-09-28). "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. ^ "Anavex Life Sciences Reports ANAVEX®2-73 (blarcamesine) featured as a Disease-Modifying Small ..." Globe Newswire. March 16, 2021. Retrieved April 2, 2021.
  9. ^ Name, Drug (28 March 2024). "ANAVEX 3-71". AdisInsight. Retrieved 12 September 2024.
  10. ^ Alexandre Vamvakides, et al. WO1997030983
  11. ^ Alexandre Vamvakides, FR2897535 (2007).
  12. ^ Αλεξανδρος Βαμβακιδης, GR1004208 (2003)
  13. ^ Jan Benes & Jiri Krepelka, CS217732 (1983).
  14. ^ [Justus Liebigs. Ann. Chem. 526, 1 (1936)]
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