Blarcamesine (development code ANAVEX2-73) is an experimental drug developed by Anavex Life Sciences. It is in

phase IIb The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

phase III trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

s for

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

and

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

, phase IIa trials for

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

phase I trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

s for

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

, and in preclinical trials for

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

and stroke. Blarcamesine acts as a

muscarinic receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...

and a moderate sigma1 receptor

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

. In trials for Alzheimer's disease, Anavex Life Sciences reported that in patients with a fully functional SIGMAR1 gene, which encodes the sigma-1 receptor targeted by blarcamesine, the drug improved cognition as measured by the mini-mental state examination by 14% after 70 weeks of treatment. Competence in

activities of daily living Activity may refer to: * Action (philosophy), in general * Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may st ...

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.

Pharmacokinetics

Blarcamesine may function as a

pro-drug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is a positional isomer of ANAVEX 1-41, which is similar to blarcamesine but it is not as selective for sigma receptor.

Properties and uses

Blarcamesine was originally tested in mice against the effect of the muscarinic receptor antagonist

scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomiting ...

, which induces learning impairment. M1 receptor agonists are known to reverse the amnesia caused by scopolamine. Scopolamine is used in the treatment of

and

motion sickness Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include d ...

by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach. This is via

competitive inhibition Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...

of muscarinic receptors. Muscarinic receptors are involved in the formation of both short term and long term memories. Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of

amyloid-beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...

and target GSK-3B. Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...

to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme is involved in the formation of Tau plaques, which are common in

. Therefore. M1 receptor activation appears to decreases tau

hyperphosphorylation Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signaling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems ...

and amyloid-beta accumulation. Sigma1 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. The sigma-1 receptor is located on

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

-associated

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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 Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which radical (chemistry), free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by ...

levels, Bax/

Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...

ratio and

cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

release into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, which are indicative of elevated toxicity. Blarcamesine inhibits mitochondrial respiratory dysfunction and therefore prevents against

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. This drug prevented the appearance of oxidative stress. Blarcamesine 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 Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...

. Results from Maurice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like

donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...

, an

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

inhibitor, or the

memantine Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...

, a

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

antagonist.

References

{{Sigma receptor modulators Muscarinic antagonists Sigma agonists Prodrugs Dimethylamino compounds