 | This article has multiple issues. Please helpimprove it or discuss these issues on thetalk page.(Learn how and when to remove these messages) (Learn how and when to remove this message)
|
 | |
| Clinical data | |
|---|---|
| Other names | ANAVEX 2-73 |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C19H23NO |
| Molar mass | 281.399 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Blarcamesine (developmental code nameANAVEX 2-73) is anexperimental drug which is under development for the treatment ofAlzheimer's disease and a variety of other indications.[1]
Blarcamesine acts as anagonist of thesigmaσ1 receptor, themuscarinic acetylcholineM1 receptor, and theionotropic glutamateNMDA receptor.[2][1]
The drug was developed by Anavex Life Sciences.[1] As of August 2024, it is inpreregistration for Alzheimer's disease,phase 2/3clinical trials forfragile X syndrome andRett syndrome, phase 2 trials forParkinson's disease, and phase 1 trials forAngelman syndrome andinfantile spasms.[1] It was also under development for the treatment ofamyotrophic lateral sclerosis (ALS),anxiety disorders,autistic spectrum disorders,cognition disorders,multiple sclerosis, andstroke, but development for these indications was discontinued.[1]
Blacarmesine acts primarily as anagonist of thesigmaσ1 receptor (affinity (IC50Tooltip half-maximal inhibitory concentration) = 860 nM).[2] To a lesser extent, it is also an agonist of themuscarinic acetylcholineM1 receptor (affinity = 5 μM) and of theionotropic glutamateNMDA receptor (affinity = 8 μM).[2]
Blarcamesine was originally tested in mice against the effect of the muscarinic receptor antagonistscopolamine, which induces learning impairment.[3] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[4] Scopolamine is used in the treatment ofParkinson's disease andmotion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[4] This is viacompetitive inhibition of muscarinic receptors.[4] Muscarinic receptors are involved in the formation of bothshort term andlong term memories.[3] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation ofβ-amyloid and targetGSK-3B.[clarification needed] Furthermore, stimulation of the M1 receptor activatesAF267B, which in turn blocksβ-secretase, which cleaves theamyloid precursor protein to produce theamyloid-beta peptide. These β-amyloid peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation ofTau plaques, which are common inAlzheimer's disease.[clarification needed][5] Therefore, M1 receptor activation appears to decreases tauhyperphosphorylation 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 onmitochondria-associatedendoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. Blarcamesine preventedAβ25-35-induced increases inlipid peroxidation levels,Bax/Bcl-2 ratio andcytochrome c release into thecytosol, which are indicative of elevated toxicity.[clarification needed] Blarcamesine inhibits mitochondrial respiratory dysfunction and therefore prevents againstoxidative stress andapoptosis. This drug prevented the appearance of oxidative stress. Blarcamesine also exhibitsanti-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 ofnuclear factor kB.[6] Results from Maurice (2016) found that σ1 receptor agonists may offer a protective potential, both alone and possibly with other agents likedonepezil, anacetylcholinesterase inhibitor, ormemantine, aNMDA receptor antagonist.[7]
Blarcamesine may function as aprodrug forANAVEX 19-144[2] as well as act as a drug itself. ANAVEX19-144 is apositional isomer ofANAVEX 1-41, which is similar to blarcamesine but is not asselective forsigmaσ1 receptor.[1]
In trials forAlzheimer's disease, Anavex Life Sciences reported that in patients with a fully functionalSIGMAR1gene, which encodes the σ1 receptor targeted by blarcamesine, the drug improved cognition as measured by themini-mental state examination (MMSE) by 14% after 70 weeks of treatment. Competence inactivities of daily living was improved by 8% in the same subgroup of patients. Additionally, in trials forParkinson's disease,episodic memory was significantly improved after 14 weeks of treatment.[8]
A related drug isANAVEX 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).
