Blarcamesine

ブラルカメシン;

[(2,2-diphenyloxolan-3-yl)methyl]dimethylamine

• Anavex 2-73
• Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethanamine
• THD-DP-FM
• AE-37 / AE37 / ANAVEX 2-73 FREE BASE
• UNII 9T210MMZ3F

Treatment of Rett syndrome, Investigated for use/treatment in breast cancer.

Anti-amnesic, Muscarinic/sigma receptor agonist

• Originator Anavex Life Sciences
• Developer ABX-CRO; Anavex Life Sciences; The Michael J. Fox Foundation for Parkinsons Research
• Class Antidementias; Antidepressants; Antiepileptic drugs; Antiparkinsonians; Anxiolytics; Behavioural disorder therapies; Dimethylamines; Furans; Neuroprotectants; Neuropsychotherapeutics; Nootropics; Small molecules
• Mechanism of Action Muscarinic receptor modulators; Sigma-1 receptor agonists

• Orphan Drug Status Yes – Epilepsy; Rett syndrome

• Phase II/III Alzheimer’s disease
• Phase II Parkinson’s disease; Rett syndrome
• Preclinical Amyotrophic lateral sclerosis; Angelman syndrome; Anxiety disorders; Autistic disorder; Fragile X syndrome; Multiple sclerosis
• No development reported Cognition disorders; Epilepsy; Stroke

• 28 Oct 2019 No recent reports of development identified for phase-I development in Cognition-disorders in USA
• 09 Oct 2019 Anavex Life Sciences initiates enrolment in the long term extension ATTENTION-AD trial for Alzheimer’s disease in (country/ies)
• 02 Oct 2019 Anavex Life Sciences has patent protection covering compositions of matter and methods of treating Alzheimer’s disease for blarcamesine in USA
• Anavex Life Sciences is developing ANAVEX-2-73 and its active metabolite ANAVEX-19-144, for treating Alzheimer’s disease, epilepsy, stroke and Rett syndrome.

ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer’s disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson’s disease, Rett syndrome, stroke.^[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.^[1] ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.^[2]

Properties and uses

ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.^[2] ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.^[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.^[3] 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.^[3] This is via competitive inhibition of muscarinic receptors.^[3] Muscarinic receptors are involved in the formation of both short term and long term memories.^[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta 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 amyloid-beta 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][4]}Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.^[4]

Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.^[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.^{[clarification needed]} ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.^[5] Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.^[6]

PATENT

WO9730983

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019200345&tab=PCTDESCRIPTION&_cid=P10-K2E5QZ-30663-1

Novel crystalline forms of A2-73 (blarcamesine hydrochloride, ANAVEX2-73, AV2-73), a mixed muscarinic receptor ligand and Sig-1 R agonist useful for treating Alzheimer’s disease.

PATENT

WO2017013498

SYN

By Foscolos, George B. et alFrom Farmaco, 51(1), 19-26; 1996

References

//////////Blarcamesine, ブラルカメシン , Orphan Drug Status, PHASE 2

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