Cutamesine: Difference between revisions

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| verifiedrevid = 426718453

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|PIN=1-[2-(3,4-Dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine

| CASNo_Ref = {{cascite|correct|??}}

| CASNo=165377-43-5

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| CASNo2 = 165377-44-6

| CASNo2_Comment =(dihydrochloride)

| UNII = 9J7A4144BX

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| UNII2 = B66RO93FXQ

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2_Comment = (dihydrochloride)

| PubChem=9954941

| SMILES=COC1=C(OC)C=C(CCN2CCN(CCCC3=CC=CC=C3)CC2)C=C1

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| C=23| H=32| N=2| O=2

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'''Cutamesine''' ('''SA 4503''') is a synthetic [[sigma receptor]] [[agonist]] which is selective for the [[Sigma-1 receptor|''σ''1 receptor]], a [[Chaperone (protein)|chaperone protein]] mainly found in the [[endoplasmic reticulum]] of cells in the [[central nervous system]].<ref name=":0">{{Cite journal|last=Skuza|first=Grazyna|date=November 2003|title=Potential antidepressant activity of sigma ligands|journal=Polish Journal of Pharmacology|volume=55|issue=6|pages=923–934|issn=1230-6002|pmid=14730086}}</ref><ref name=":1">{{Cite web|url=http://www.chemspider.com/Chemical-Structure.8082975.html|title=cutamesine {{!}} C23H32N2O2 {{!}} ChemSpider|website=www.chemspider.com|access-date=2019-06-12}}</ref><ref name=":2">{{Cite journal|last1=Hayashi|first1=Teruo|last2=Su|first2=Tsung-Ping|date=November 2007|title=Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival|journal=Cell|volume=131|issue=3|pages=596–610|doi=10.1016/j.cell.2007.08.036|pmid=17981125|s2cid=18885068|doi-access=free}}</ref><ref name=":3">{{Cite journal|last1=Weissman|first1=A. D.|last2=Su|first2=T. P.|last3=Hedreen|first3=J. C.|last4=London|first4=E. D.|date=October 1988|title=Sigma receptors in post-mortem human brains|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=247|issue=1|pages=29–33|issn=0022-3565|pmid=2845055}}</ref> These ''σ''1 receptors play a key role in the modulation of Ca²⁺ release and apoptosis.<ref name=":2" /> Cutamesine's activation of the ''σ''1 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.<ref name=":4">{{Cite journal|last1=Skuza|first1=G.|last2=Wedzony|first2=K.|date=November 2004|title=Behavioral Pharmacology of σ-Ligands|journal=Pharmacopsychiatry|volume=37|issue=S 3|pages=183–188|doi=10.1055/s-2004-832676|pmid=15547784|s2cid=87032896 |issn=0176-3679}}</ref><ref name=":5">{{Cite journal|last1=Tuerxun|first1=Tuerhong|last2=Numakawa|first2=Tadahiro|last3=Adachi|first3=Naoki|last4=Kumamaru|first4=Emi|last5=Kitazawa|first5=Hiromi|last6=Kudo|first6=Motoshige|last7=Kunugi|first7=Hiroshi|date=January 2010|title=SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression|journal=Neuroscience Letters|volume=469|issue=3|pages=303–308|doi=10.1016/j.neulet.2009.12.013|pmid=20025928|s2cid=20552121}}</ref>

== Structure ==

The molecular formula for cutamesine is C₂₃H₃₂N₂O₂.<ref name=":1" /> This particular agonist is a [[piperazine]], meaning that its core functional group is a six-membered heterocycle with two oppositely-placed nitrogen atoms. Two phenalkyl groups act as substituents for the two nitrogen atoms. The phenethyl group has [[methoxy group]]s on the 3 and 4 locations of the aromatic ring, while the phenpropyl group has no additional functional groups attached.[[File:Sigma Receptor.png|thumb|Cutamesine (yellow) exhibits preferential binding to the sigma-1 receptor (blue). The piperazine ring interacts with the amine binding site (green), and the phenalkyl groups interact with two of the three hydrophobic pockets (red).|alt=|237x237px|left]]

== Affinity ==

=== Causes of Affinity ===

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 to ''σ''1.<ref name=":8">{{Cite journal|last1=Xu|first1=Rong|last2=Lord|first2=Sarah A.|last3=Peterson|first3=Ryan M.|last4=Fergason-Cantrell|first4=Emily A.|last5=Lever|first5=John R.|last6=Lever|first6=Susan Z.|date=January 2015|title=Ether modifications to 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503): Effects on binding affinity and selectivity for sigma receptors and monoamine transporters|journal=Bioorganic & Medicinal Chemistry|volume=23|issue=1|pages=222–230|doi=10.1016/j.bmc.2014.11.007|pmc=4274187|pmid=25468036}}</ref> Replacement side groups that possess the most [[Steric effects|steric bulk]] have the lowest binding affinity for the ''σ''1 receptor.<ref name=":8" /> 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 to ''σ''1.<ref name=":6">{{Cite journal|last1=Ablordeppey|first1=Seth Y|last2=Fischer|first2=James B|last3=Glennon|first3=Richard A|date=August 2000|title=Is a Nitrogen Atom an Important Pharmacophoric Element in Sigma Ligand Binding?|journal=Bioorganic & Medicinal Chemistry|volume=8|issue=8|pages=2105–2111|doi=10.1016/S0968-0896(00)00148-6|pmid=11003156}}</ref> N(b) - the nitrogen in the piperazine attached to the longest substituent - plays a much greater role in binding affinity than N(a).<ref name=":6" /> Sigma receptors are defined by the presence of one amine binding site and three hydrophobic binding sites nearby in the ligand-binding region.<ref name=":3" /> 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 two out of the three hydrophobic pockets.<ref name=":2" />

=== Binding Trends ===

Cutamesine exhibits high binding affinity for the ''σ''1 receptor, with greatly reduced affinity for the ''σ''2 receptor.<ref name=":7">{{Cite journal|last1=Matsuno|first1=Kiyoshi|last2=Nakazawa|first2=Minako|last3=Okamoto|first3=Kazuyoshi|last4=Kawashima|first4=Yoichi|last5=Mita|first5=Shiro|date=June 1996|title=Binding properties of SA4503, a novel and selective σ1 receptor agonist|journal=European Journal of Pharmacology|volume=306|issue=1–3|pages=271–279|doi=10.1016/0014-2999(96)00201-4|pmid=8813641}}</ref> It acts as a competitive inhibitor for (+)-[3H]pentazocine.<ref name=":7" /> [[Haloperidol]] and NE-100 antagonize cutamesine-induced cholinergic ([[acetylcholine]]) facilitation.<ref name=":7" /> Cutamesine likely does not interact directly with cholinergic receptors, as its binding affinity for them is nearly non-existent.<ref>{{Cite journal|last1=Horan|first1=Bryan|last2=Gifford|first2=Andrew N.|last3=Matsuno|first3=Kiyoshi|last4=Mita|first4=Shiro|last5=Ashby|first5=Charles R.|date=October 2002|title=Effect of SA4503 on the electrically evoked release of3H-acetylcholine from striatal and hippocampal rat brain slices|journal=Synapse|volume=46|issue=1|pages=1–3|doi=10.1002/syn.10107|pmid=12211092|s2cid=41458292 |issn=0887-4476}}</ref> It can also bind to vertebral [[emopamil]] binding protein (EBP).<ref name=":9">{{Cite journal|last1=Toyohara|first1=Jun|last2=Sakata|first2=Muneyuki|last3=Ishiwata|first3=Kiichi|date=October 2012|title=Re-evaluation of in vivo selectivity of [11C]SA4503 to σ1 receptors in the brain: Contributions of emopamil binding protein|journal=Nuclear Medicine and Biology|volume=39|issue=7|pages=1049–1052|doi=10.1016/j.nucmedbio.2012.03.002|pmid=22497960}}</ref> Although EBP exists at a lower density in the brain than ''σ''1 receptors, cutamesine exhibits higher affinity for the former.<ref name=":9" />

== Physiological Effects ==

=== Memory and Amnesia ===

It has been shown that cutamesine has anti-amnesic properties and could be used to reduce the effects of amnesia caused by [[Rapid eye movement sleep|REM sleep]] deprivation.<ref>{{Cite journal|last1=Ramakrishnan|first1=Nisha K.|last2=Schepers|first2=Marianne|last3=Luurtsema|first3=Gert|last4=Nyakas|first4=Csaba J.|last5=Elsinga|first5=Philip H.|last6=Ishiwata|first6=Kiichi|last7=Dierckx|first7=Rudi A. J. O.|last8=van Waarde|first8=Aren|date=June 2015|title=Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy|journal=Molecular Imaging and Biology|volume=17|issue=3|pages=364–372|doi=10.1007/s11307-014-0808-2|pmid=25449772|s2cid=826030|issn=1536-1632}}</ref> Decreases in the memory function of rats caused by the presence of [[Hyoscine|scopolamine]] has been shown to be mitigated by the introduction of SA 4503.<ref>{{Cite journal|last1=Matsuno|first1=Kiyoshi|last2=Senda|first2=Toshihiko|last3=Kobayashi|first3=Tetsuya|last4=Okamoto|first4=Kazuyoshi|last5=Nakata|first5=Katsuhiko|last6=Mita|first6=Shiro|date=February 1997|title=SA4503, a novel cognitive enhancer, with σ1 receptor agonistic properties|journal=Behavioural Brain Research|volume=83|issue=1–2|pages=221–224|doi=10.1016/S0166-4328(97)86074-3|pmid=9062689|s2cid=54240821}}</ref> The activation of the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway in neurons is repressed by SA 4503, which in turn leads to reduced stress-related cell death.<ref name=":5" /> The presence of SA 4503 has a positive impact on the number of active [[Dopaminergic cell groups|dopaminergic neurons]] in the [[Frontal lobe|frontal cortex]], which is linked to improved memory function.<ref name=":4" />[[File:Forced-swimming test.jpg|thumb|Rodents that were administered cutamesine had a lower immobility time than the control.|alt=|184x184px]]

=== Depression ===

''σ''1 receptors are of interest to scientists studying the neurology of depression, as certain antidepressants (ADs) exhibit high affinity for these receptors and ''σ''1 receptor agonists such as SA 4503 have displayed activity similar to that of ADs in non-human trials.<ref>{{Cite journal|last1=Rogóż|first1=Zofia|last2=Skuza|first2=Grażyna|last3=Maj|first3=Jerzy|last4=Danysz|first4=Wojciech|date=June 2002|title=Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats|journal=Neuropharmacology|volume=42|issue=8|pages=1024–1030|doi=10.1016/S0028-3908(02)00055-2|pmid=12128003|s2cid=20376278}}</ref> The function of dopaminergic systems has been linked to the effectiveness of ADs, and many experiments involving cutamesine have revolved around dopamine.<ref name=":0" /> The presence of SA 4503 has been linked to increases in the concentration of dopamine and dihydroxyphenylacetic acid (a metabolite of dopamine) in the frontal cortex.<ref name=":0" /> Cutamesine may assist with the release of dopamine from [[Chemical synapse|presynaptic neurons]] in the frontal cortex.<ref name=":0" /> For rodents, there was a negative correlation between SA 4503 levels and immobility time during a [[Behavioural despair test|forced swimming test]].<ref name=":0" />

=== Heart ===

The administration of cutamesine has been shown to mitigate the effects of cardiac [[hypertrophy]].<ref name=":10">{{Cite journal|last1=Hirano|first1=Kohga|last2=Tagashira|first2=Hideaki|last3=Fukunaga|first3=Kohji|date=2014|title=Cardioprotective Effect of the Selective Sigma-1 Receptor Agonist, SA4503|journal=Yakugaku Zasshi|volume=134|issue=6|pages=707–713|doi=10.1248/yakushi.13-00255-3|pmid=24882645|issn=0031-6903|doi-access=free}}</ref> [[Angiotensin|Angiotensin II]]-induced hypertrophy results in lower [[Adenosine triphosphate|ATP]] production and smaller mitochondrial size in [[Cardiac muscle cell|cardiomyocytes]], and introduction of SA 4503 returns both ATP production and mitochondrial size to baseline.<ref name=":10" />

=== Hearing ===

The presence of cutamesine is positively correlated with the presence of [[Hippocampus|hippocampal]] brain‐derived [[Neurotrophic factors|neurotrophic factor]] (BDNF).<ref name=":11">{{Cite journal|last1=Yamashita|first1=Daisuke|last2=Sun|first2=Guang-wei|last3=Cui|first3=Yong|last4=Mita|first4=Shiro|last5=Otsuki|first5=Naoki|last6=Kanzaki|first6=Sho|last7=Nibu|first7=Ken-ichi|last8=Ogawa|first8=Kaoru|last9=Matsunaga|first9=Tatsuo|date=May 2015|title=Neuroprotective effects of cutamesine, a ligand of the sigma-1 receptor chaperone, against noise-induced hearing loss: Cutamesine Protects Against Hearing Loss|journal=Journal of Neuroscience Research|volume=93|issue=5|pages=788–795|doi=10.1002/jnr.23543|pmid=25612541|s2cid=206130476 |doi-access=free}}</ref> 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.<ref name=":11" /> Despite the apparent auditory benefits of cutamesine treatment, it does not prevent hearing loss that is a result of aging.<ref name=":11" />

{{Sigma receptor modulators}}

[[Category:Catechol ethers]]

[[Category:Phenethylamines]]