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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. Developed by Santen Pharmaceutical, its presence and activation of the σ1 receptor are tied to a variety of physiological phenomena in the central nervous system, including activation of dopamine-releasing neurons and repression of the MAPK/ERK pathway.

Structure
The molecular formula for cutamesine is C23H32N2O2. Cutamesine is a piperazine, meaning that its core functional group is a six-membered ring with two oppositely-placed nitrogen atoms. Two phenethyl groups act as substituents for the two nitrogen atoms. One of the phenethyl groups has methoxy groups in the 3 and 4 locations on the aromatic ring. The nitrogen atoms in the molecule play a central role in its affinity, as removal of these nitrogen atoms results in a lack of affinity. N(b) - the nitrogen in the piperazine attached to the longest substituent - plays a much greater role in binding affinity than N(a). Sigma receptors are defined by the presence of one amine binding site and three hydrophobic binding sites nearby.[4] Thus, the N(b) atom in the central piperazine ring serves to interact with the amine binding site and the two phenethyl groups serve to fill the hydrophobic pockets.[3]

Affinity
Cutamesine exhibits high binding affinity for the σ1 receptor, with greatly reduced affinity for the σ2 receptor. It acts as a competitive inhibitor for (+)-[3H]pentazocine. The 3,4-methoxy groups located on the phenethyl group play an important role in σ receptor binding affinity, with alterations made to these groups leading to changes in affinity. Replacement side groups that possess the most steric bulk and non-polarity result in the lowest binding affinity for the σ1 receptor. Haloperidol and NE-100 antagonize cutamesine-induced cholinergic faciliation. Cutamesine likely does not interact directly with cholinergic receptors, as its binding affinity for them is nearly non-existent. SA 4503 can also bind to vertebral emopamil binding protein (EBP). Although EBP exists at a lower density in the brain than σ1 receptors, cutamesine exhibits higher affinity for the former.

Memory and Amnesia
Sigma-1 receptor agonists can treat amnesic problems. It has been shown that cutamesine has anti-amnesic properties and could be used to reduce the effects of amnesia caused by REM sleep deprivation. Decreases in the memory function of rats caused by the presence of scopolamine has been shown to be mitigated by the introduction of SA 4503. The activation of the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway in neurons is repressed by SA 4503. The presence of SA 4503 has a positive impact on the number of active dopaminergic neurons in the frontal cortex.

Depression
σ1 receptors are of interest to scientists studying the neurology of depression, as antidepressants (ADs) exhibit high affinity for these receptors and σ1 receptor agonists such as SA 4503 have displayed activity similar to that of ADs in non-human trials. The presence of SA 4503 has been linked to increases in the concentration of dopamine and dihydroxyphenylacetic acid in the frontal cortex. Cutamesine may assist with the release of dopamine from presynaptic neurons in the frontal cortex. For rodents, there was a negative correlation between SA 4503 levels and immobility time during a forced swimming test.

Heart
The administration of cutamesine has been shown to mitigate the effects of cardiac hypertrophy. Angiotension II-induced hypertrophy results in lower ATP production and smaller mitochondrial size in cardiomyocytes, and introduction of SA 4503 returns both ATP production and mitochondrial size to baseline.

Hearing
The presence of cutamesine is positively correlated with the presence of hippocampal brain‐derived neurotrophic factor (BDNF).[11] Due to the relationship between the presence of BDNF and ciliary neurotrophic factor and the preservation of auditory nerves, it is thought that cutamesine may have a positive effect on the health of the cochlea.[10] Despite the apparent auditory benefits of cutamesine treatment, it does not prevent hearing loss that is a result of aging.