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| Names | |
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| IUPAC name
1-[2-(3,4-Dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.[1][2][3][4] 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.[5][6]
Structure
editThe molecular formula for cutamesine is C23H32N2O2.[2] 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.[7] N(b) - the nitrogen in the piperazine attached to the longest substituent - plays a much greater role in binding affinity than N(a).[7] 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
editCutamesine exhibits high binding affinity for the σ1 receptor, with greatly reduced affinity for the σ2 receptor.[8] It acts as a competitive inhibitor for (+)-[3H]pentazocine.[8] 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.[9] Replacement side groups that possess the most steric bulk and non-polarity result in the lowest binding affinity for the σ1 receptor.[9] Haloperidol and NE-100 antagonize cutamesine-induced cholinergic faciliation.[8] Cutamesine likely does not interact directly with cholinergic receptors, as its binding affinity for them is nearly non-existent.[10] SA 4503 can also bind to vertebral emopamil binding protein (EBP).[11] Although EBP exists at a lower density in the brain than σ1 receptors, cutamesine exhibits higher affinity for the former.[11]
Physiological Effects
editMemory and Amnesia
editSigma-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.[12] 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.[13] The activation of the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway in neurons is repressed by SA 4503.[6] The presence of SA 4503 has a positive impact on the number of active dopaminergic neurons in the frontal cortex.[5]
Depression
editσ1 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.[14] The presence of SA 4503 has been linked to increases in the concentration of dopamine and dihydroxyphenylacetic acid in the frontal cortex.[1] Cutamesine may assist with the release of dopamine from presynaptic neurons in the frontal cortex.[1] For rodents, there was a negative correlation between SA 4503 levels and immobility time during a forced swimming test.[1]
Heart
editThe administration of cutamesine has been shown to mitigate the effects of cardiac hypertrophy.[15] 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.[15]
Hearing
editThe 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.[16]
References
edit- ^ a b c d Skuza, Grazyna (2003-11). "Potential antidepressant activity of sigma ligands". Polish Journal of Pharmacology. 55 (6): 923–934. ISSN 1230-6002. PMID 14730086.
{{cite journal}}: Check date values in:|date=(help) - ^ a b "cutamesine | C23H32N2O2 | ChemSpider". www.chemspider.com. Retrieved 2019-05-15.
- ^ Hayashi, Teruo; Su, Tsung-Ping (2007-11). "Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival". Cell. 131 (3): 596–610. doi:10.1016/j.cell.2007.08.036.
{{cite journal}}: Check date values in:|date=(help) - ^ Weissman, A. D.; Su, T. P.; Hedreen, J. C.; London, E. D. (1988-10). "Sigma receptors in post-mortem human brains". The Journal of Pharmacology and Experimental Therapeutics. 247 (1): 29–33. ISSN 0022-3565. PMID 2845055.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Skuza, G.; Wedzony, K. (2004-11). "Behavioral Pharmacology of σ-Ligands". Pharmacopsychiatry. 37 (S 3): 183–188. doi:10.1055/s-2004-832676. ISSN 0176-3679.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Tuerxun, Tuerhong; Numakawa, Tadahiro; Adachi, Naoki; Kumamaru, Emi; Kitazawa, Hiromi; Kudo, Motoshige; Kunugi, Hiroshi (2010-01). "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". Neuroscience Letters. 469 (3): 303–308. doi:10.1016/j.neulet.2009.12.013. ISSN 0304-3940.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Ablordeppey, Seth Y; Fischer, James B; Glennon, Richard A (2000-08). "Is a Nitrogen Atom an Important Pharmacophoric Element in Sigma Ligand Binding?". Bioorganic & Medicinal Chemistry. 8 (8): 2105–2111. doi:10.1016/s0968-0896(00)00148-6. ISSN 0968-0896.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c Matsuno, Kiyoshi; Nakazawa, Minako; Okamoto, Kazuyoshi; Kawashima, Yoichi; Mita, Shiro (1996-6). "Binding properties of SA4503, a novel and selective σ1 receptor agonist". European Journal of Pharmacology. 306 (1–3): 271–279. doi:10.1016/0014-2999(96)00201-4.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Xu, Rong; Lord, Sarah A.; Peterson, Ryan M.; Fergason-Cantrell, Emily A.; Lever, John R.; Lever, Susan Z. (2015-01). "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". Bioorganic & Medicinal Chemistry. 23 (1): 222–230. doi:10.1016/j.bmc.2014.11.007. ISSN 0968-0896.
{{cite journal}}: Check date values in:|date=(help) - ^ Horan, Bryan; Gifford, Andrew N.; Matsuno, Kiyoshi; Mita, Shiro; Ashby, Charles R. (2002-07-25). "Effect of SA4503 on the electrically evoked release of3H-acetylcholine from striatal and hippocampal rat brain slices". Synapse. 46 (1): 1–3. doi:10.1002/syn.10107. ISSN 0887-4476.
- ^ a b Toyohara, Jun; Sakata, Muneyuki; Ishiwata, Kiichi (2012-10). "Re-evaluation of in vivo selectivity of [11C]SA4503 to σ1 receptors in the brain: Contributions of emopamil binding protein". Nuclear Medicine and Biology. 39 (7): 1049–1052. doi:10.1016/j.nucmedbio.2012.03.002. ISSN 0969-8051.
{{cite journal}}: Check date values in:|date=(help) - ^ Ramakrishnan, Nisha K.; Schepers, Marianne; Luurtsema, Gert; Nyakas, Csaba J.; Elsinga, Philip H.; Ishiwata, Kiichi; Dierckx, Rudi A. J. O.; van Waarde, Aren (2015-6). "Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy". Molecular Imaging and Biology. 17 (3): 364–372. doi:10.1007/s11307-014-0808-2. ISSN 1536-1632.
{{cite journal}}: Check date values in:|date=(help) - ^ Matsuno, Kiyoshi; Senda, Toshihiko; Kobayashi, Tetsuya; Okamoto, Kazuyoshi; Nakata, Katsuhiko; Mita, Shiro (1997-02). "SA4503, a novel cognitive enhancer, with σ1 receptor agonistic properties". Behavioural Brain Research. 83 (1–2): 221–224. doi:10.1016/s0166-4328(97)86074-3. ISSN 0166-4328.
{{cite journal}}: Check date values in:|date=(help) - ^ Rogóż, Zofia; Skuza, Grażyna; Maj, Jerzy; Danysz, Wojciech (2002-06). "Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats". Neuropharmacology. 42 (8): 1024–1030. doi:10.1016/s0028-3908(02)00055-2. ISSN 0028-3908.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Hirano, Kohga; Tagashira, Hideaki; Fukunaga, Kohji (2014). "Cardioprotective Effect of the Selective Sigma-1 Receptor Agonist, SA4503". YAKUGAKU ZASSHI. 134 (6): 707–713. doi:10.1248/yakushi.13-00255-3. ISSN 0031-6903.
- ^ Yamashita, Daisuke; Sun, Guang-wei; Cui, Yong; Mita, Shiro; Otsuki, Naoki; Kanzaki, Sho; Nibu, Ken-ichi; Ogawa, Kaoru; Matsunaga, Tatsuo (2015-01-22). "Neuroprotective effects of cutamesine, a ligand of the sigma-1 receptor chaperone, against noise-induced hearing loss". Journal of Neuroscience Research. 93 (5): 788–795. doi:10.1002/jnr.23543. ISSN 0360-4012.