Blarcamesine

Last updated
Blarcamesine
ANAVEX2-73.svg
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
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 a variety of 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

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]

Pharmacokinetics

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

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

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

Related Research Articles

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Donepezil</span> Medication used for dementia

Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

<span class="mw-page-title-main">Memantine</span> Medication used to treat Alzheimers disease

Memantine, sold under the brand name Axura among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP, SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

<span class="mw-page-title-main">Muscarinic agonist</span> Activating agent of the muscarinic acetylcholine receptor

A muscarinic agonist is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.

<span class="mw-page-title-main">Sigma-1 receptor</span> Chaperone protein

The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the SIGMAR1 gene.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

Cutamesine (SA 4503) is a synthetic sigma receptor agonist which is selective for the σ1 receptor, a chaperone protein mainly found in the endoplasmic reticulum of cells in the central nervous system. These σ1 receptors play a key role in the modulation of Ca2+ release and apoptosis. Cutamesine's activation of the σ1 receptor is tied to a variety of physiological phenomena in the CNS, including activation of dopamine-releasing neurons and repression of the MAPK/ERK pathway.

<span class="mw-page-title-main">Sigma-2 receptor</span> Protein-coding gene in the species Homo sapiens

The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as neurological diseases, neurodegenerative, neuro-ophthalmic and cancer. It is currently under investigation for its potential diagnostic and therapeutic uses.

<span class="mw-page-title-main">Xanomeline</span> Chemical compound

Xanomeline is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system disorders.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

<span class="mw-page-title-main">Talsaclidine</span> Chemical compound

Talsaclidine (WAL-2014) is a non-selective muscarinic acetylcholine receptor agonist which acts as a full agonist at the M1 subtype, and as a partial agonist at the M2 and M3 subtypes. It was under development for the treatment of Alzheimer's disease but showed only modest or poor efficacy in rhesus monkeys and humans, respectively, perhaps due to an array of dose-limiting side effects including increased heart rate and blood pressure, increased salivation, urinary frequency and burning upon urination, increased lacrimation and nasal secretion, abnormal accommodation, heartburn, upset stomach as well as cramps, nausea, vomiting and diarrhea, excessive sweating and palpitations.

CI-1017 is a muscarinic acetylcholine receptor agonist which is selective for and is approximately equipotent at the M1 and M4 receptors, with 20-30-fold lower affinity for the M2, M3, and M5 subtypes It is the (R)-enantiomer of the racemic compound PD-142,505.

<span class="mw-page-title-main">Clinical neurochemistry</span>

Clinical neurochemistry is the field of neurological biochemistry which relates biochemical phenomena to clinical symptomatic manifestations in humans. While neurochemistry is mostly associated with the effects of neurotransmitters and similarly functioning chemicals on neurons themselves, clinical neurochemistry relates these phenomena to system-wide symptoms. Clinical neurochemistry is related to neurogenesis, neuromodulation, neuroplasticity, neuroendocrinology, and neuroimmunology in the context of associating neurological findings at both lower and higher level organismal functions.

<span class="mw-page-title-main">Nitromemantine</span> Chemical compound

Nitromemantine is a derivative of memantine developed in 2006 for the treatment of Alzheimer's disease. It has been shown to reduce excitotoxicity mediated by over-activation of the glutamatergic system, by blocking NMDA receptors.

<span class="mw-page-title-main">Cholinergic neuron</span> Type of nerve cell

A cholinergic neuron is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic. Cholinergic neurons provide the primary source of acetylcholine to the cerebral cortex, and promote cortical activation during both wakefulness and rapid eye movement sleep. The cholinergic system of neurons has been a main focus of research in aging and neural degradation, specifically as it relates to Alzheimer's disease. The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in Alzheimer's disease.

The ion channel hypothesis of Alzheimer's disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.

Xanomeline/trospium, also known under the brand name KarXT, is an investigational oral dual-drug fixed-dose combination of xanomeline and trospium. It is undergoing a phase 3 clinical trial for the treatment of schizophrenia. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist that readily passes into the central nervous system (CNS) to stimulate these receptors in key areas of the brain. Trospium is a non-selective muscarinic antagonist that does not cross into the CNS and reduces peripheral cholinergic side effects associated with xanomeline.

References

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  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 2015-11-12. Retrieved 2016-05-25.
  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.
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  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.