Chemistry:Salsolinol

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Salsolinol
Salsolinol.svg
Names
Other names
6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline
Identifiers
3D model (JSmol)
UNII
Properties
C10H13NO2
Molar mass 179.22 g/mol
Melting point 147-149°C [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Salsolinol is a chemical compound derived from dopamine which plays a role in neurotransmission and is neurotoxic.

It has been linked to dopamine-related disorders including Parkinson's disease and alcohol use disorder. It is both synthesized in the human body and ingested in several common dietary sources.[2]

Chemistry and structure

Salsolinol is a catechol isoquinoline which is a yellow solid at room temperature.[1] Salsolinol, as a chiral molecule, comes in two enantiomers: (R)-salsolinol and (S)-salsolinol. The two may have different biological effects.

The racemate can be synthesized via a Pictet-Spengler reaction.[3] A chemoenzymatic, enantioselective synthesis of the (R)-enantiomer has also been reported.[4] Salsolinol has been used as a starting material to prepare some tetrahydroisoquinoline-based prospective drugs.[5][6]

Biochemistry

Natural occurrence

Salsolinol is found in several edible plants, most prominently bananas and cocoa products as well as beer.[7][8][9] Other plants, including black cohosh, which is used in many herbal remedies, also contain salsolinol.[10]

Biosynthesis

Salsolinol is endogenously synthesized by multiple routes, although its origin in the human body remains controversial. There are two main routes for its production: one which is through a non-enantiospecific Pictet-Spengler reaction of dopamine and acetaldehyde, and one which is mediated by the enzyme salsolinol synthase.[11]

Salsolinol synthase exclusively produces the (R)-enantiomer of salsolinol.

It has been speculated that salsolinol may also arise from salsolinol-1-carboxylic acid, which is formed by the reaction of dopamine and pyruvic acid. This transformation would occur via a proposed enzymatic pathway that has not been elucidated yet.[11]

Metabolism

Salsolinol is metabolized by an N-methyltransferase enzyme into N-methyl-(R)-salsolinol. This can then be converted by an amine oxidase into 1,2-dimethyl-6,7-dihydroxyisoquinolinium (DMDHIQ+). It can also be methylated to form its 7-methoxy and 6-methoxy versions by the enzyme catechol-O-methyltransferase (COMT).[12][11]

Salsolinol metabolism

Role in the body

Neurotoxicity and neurotransmission

Salsolinol binds to several receptors associated with dopaminergic pathways.[2][13] It may be an agonist of the μ-opioid receptor and of dopaminergic D1 and D3 receptors.[2]

Salsolinol itself also appears to be neurotoxic, the mechanism of which is not clear. Its metabolites, including N-methyl-(R)-salsolinol, also exhibit neurotoxic effects.

Prolactin

Salsolinol has been shown to be involved in the secretion of prolactin in the pituitary gland in lactating rats and lactating sheep.[14][15] Administration of a solution of salsolinol was not shown to raise prolactin levels in human women.[16]

Disease and disorders

Parkinson's disease

Salsolinol is detectable in the cerebrospinal fluid of Parkinson's disease (PD) patients and is involved in the pathogenesis of PD.[17] It is known to exercise inhibitory effects on tyrosine hydroxylase[18] and to be toxic to dopaminergic neurons.[19] A mechanism for the induction of Parkinson's by salsolinol is linked to its mediation of pyroptosis.[20]

Alcohol intake and alcohol use disorders

The connection between salsolinol and alcohol intake remains controversial. An early hypothesis was that the synthesis of salsolinol in the human body was caused by ethanol consumption, because it was being made from dopamine and acetaldehyde (a metabolite of ethanol). Several studies in the 1970s and 80s would seem to corroborate this link. However, no consistent connection between ethanol intake and salsolinol levels were conclusively established. As of the 2020s, it is understood that the primary contributor to levels of salsolinol in blood plasma is dietary intake, not acute ethanol consumption.[21] Part of the challenge in studying this is that salsolinol also is produced endogenously, and in all cases its levels are very low, making it difficult to detect and quantify with precision.[22]

Further confounding the issue, there is evidence that salsolinol may be implicated in alcohol use disorder and may play a role in increasing cravings for ethanol. (R)-Salsolinol stereospecifically induces behavioral sensitization and leads to excessive alcohol intake in rats.[23]

See also

References

  1. ↑ 1.0 1.1 Pesnot, Thomas; Gershater, Markus C.; Ward, John M.; Hailes, Helen C. (2011). "Phosphate mediated biomimetic synthesis of tetrahydroisoquinoline alkaloids". Chemical Communications 47 (11): 3242–3244. doi:10.1039/C0CC05282E. PMID 21270984. https://pubs.rsc.org/en/content/articlelanding/2011/cc/c0cc05282e. Retrieved 24 January 2024. 
  2. ↑ 2.0 2.1 2.2 Kurnik-Łucka, Magdalena; Panula, Pertti; Bugajski, Andrzej; Gil, Krzysztof (2018). "Salsolinol: an Unintelligible and Double-Faced Molecule—Lessons Learned from In Vivo and In Vitro Experiments". Neurotoxicity Research 33 (2): 485–514. doi:10.1007/s12640-017-9818-6. PMID 29063289. https://link.springer.com/article/10.1007/s12640-017-9818-6. Retrieved 31 January 2024. 
  3. ↑ Yang, Er-Lan; Sun, Bin et al. (2019). "Synthesis, Purification, and Selective β2-AR Agonist and Bronchodilatory Effects of Catecholic Tetrahydroisoquinolines from Portulaca oleracea". Journal of Natural Products 82 (11): 2986–2993. doi:10.1021/acs.jnatprod.9b00418. https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00418. Retrieved 28 January 2024. 
  4. ↑ Ding, Wei; Li, Mingze; Dai, Rongji; Deng, Yulin (2012). "Lipase-catalyzed synthesis of the chiral tetrahydroisoquinoline (R)-salsolinol". Tetrahedron: Asymmetry 23 (18): 1376–1379. doi:10.1016/j.tetasy.2012.09.009. https://www.sciencedirect.com/science/article/abs/pii/S0957416612004648. Retrieved 28 January 2024. 
  5. ↑ Madácsi, Ramóna; Kanizsai, Iván et al. (2013). "Aromatic Sulfonamides Containing a Condensed Piperidine Moiety as Potential Oxidative Stress-Inducing Anticancer Agents". Medicinal Chemistry 9 (7): 911–919. doi:10.2174/1573406411309070004. PMID 23270324. https://www.eurekaselect.com/article/55683. Retrieved 28 January 2024. 
  6. ↑ Berger, Dan; Citarella, Ron et al. (1999). "Novel Multidrug Resistance Reversal Agents". Journal of Medicinal Chemistry 42 (12): 2145–2161. doi:10.1021/jm9804477. PMID 10377220. https://pubs.acs.org/doi/10.1021/jm9804477. Retrieved 28 January 2024. 
  7. ↑ Vázquez-Manjarrez, N.; Ulaszewska, M.; Garcia-Aloy, M.; Mattivi, F.; Praticò, G.; Dragsted, L. O.; Manach, C. (2020). "Biomarkers of Intake for Tropical Fruits". Genes and Nutrition 15 (11). doi:10.1186/s12263-020-00670-4. PMID 32560627. 
  8. ↑ Strolin Benedetti, M.; Dostert, P.; Carminati, P. (1989). "Influence of food intake on the enantiomeric composition of urinary salsolinol in man". Journal of Neural Transmission 78 (1): 43–51. doi:10.1007/BF01247112. PMID 2754429. https://link.springer.com/article/10.1007/BF01247112. 
  9. ↑ Sojo, M. Mar; Nuñez-Delicado, Estrella; Sánchez-Ferrer, Alvaro; García-Carmona, Francisco (2000). "Oxidation of Salsolinol by Banana Pulp Polyphenol Oxidase and Its Kinetic Synergism with Dopamine". J. Agric. Food Chem. 48 (11): 5543–5547. doi:10.1021/jf000293f. PMID 11087516. https://pubs.acs.org/doi/10.1021/jf000293f. Retrieved 31 January 2024. 
  10. ↑ Gödecke, Tanja; Lankin, David C. et al. (2009). "Guanidine Alkaloids and Pictet−Spengler Adducts from Black Cohosh (Cimicifuga racemosa)". Journal of Natural Products 72 (3): 433–437. doi:10.1021/np8006952. PMID 19220011. 
  11. ↑ 11.0 11.1 11.2 Chen, Xuechai; Zheng, Xiaotong et al. (2018). "Isolation and Sequencing of Salsolinol Synthase, an Enzyme Catalyzing Salsolinol Biosynthesis". ACS Chemical Neuroscience 9 (6): 1388–1398. doi:10.1021/acschemneuro.8b00023. PMID 29602279. https://pubs.acs.org/doi/10.1021/acschemneuro.8b00023. Retrieved 28 January 2024. 
  12. ↑ Mravec, Boris (2005). "Salsolinol, a Derivate of Dopamine, is a Possible Modulator of Catecholaminergic Transmission: a Review of Recent Developments". Physiological Research 55: 353–364. ISSN 0862-8408. https://www.biomed.cas.cz/physiolres/pdf/55/55_353.pdf. Retrieved 28 January 2024. 
  13. ↑ Homicskó, Krisztián Gy.; Kertész, István et al. (2003). "Binding site of salsolinol: its properties in different regions of the brain and the pituitary gland of the rat". Neurochemistry International 42 (1): 19–26. doi:10.1016/S0197-0186(02)00063-3. PMID 12441164. https://www.sciencedirect.com/science/article/pii/S0197018602000633. Retrieved 24 January 2024. 
  14. ↑ Oláh, Márk; Bodnár, Ibolya et al. (2011). "Role of salsolinol in the regulation of pituitary prolactin and peripheral dopamine release". Reproductive Medicine and Biology 10 (3): 143–151. doi:10.1007/s12522-011-0086-5. PMID 29662355. 
  15. ↑ Hasiec, Małgorzata; Herman, Andrzej P. et al. (2012). "The stimulatory effect of salsolinol on prolactin gene expression within the anterior pituitary of lactating sheep: In vivo and in vitro study". Small Ruminant Research 102 (2): 202–207. doi:10.1016/j.smallrumres.2011.07.011. https://www.sciencedirect.com/science/article/pii/S0921448811002677. Retrieved 24 January 2024. 
  16. ↑ Carlson, Harold E.; Wasser, Harris L.; Reidelberger, Roger D. (1985). "Beer-Induced Prolactin Secretion: A Clinical and Laboratory Study of the Role of Salsolinol". J. Clin. Endocrinol. Metab. 60 (4): 673–677. doi:10.1210/jcem-60-4-673. PMID 3972968. https://academic.oup.com/jcem/article/60/4/673/2674814. Retrieved 24 January 2024. 
  17. ↑ Moser, A; Kömpf, D (1992). "Presence of methyl-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, derivatives of the neurotoxin isoquinoline, in parkinsonian lumbar CSF". Life Sciences 50 (24): 1885–1891. doi:10.1016/0024-3205(92)90549-5. PMID 1598074. https://dx.doi.org/10.1016/0024-3205%2892%2990549-5. Retrieved 29 January 2024. 
  18. ↑ Briggs, Gabrielle D.; Nagy, Georgy M.; Dickson, Phillip W. (2013). "Mechanism of action of salsolinol on tyrosine hydroxylase". Neurochemistry International 63 (8): 726–731. doi:10.1016/j.neuint.2013.09.016. PMID 24083987. https://www.sciencedirect.com/science/article/pii/S019701861300243X. Retrieved 24 January 2024. 
  19. ↑ Getachew, Bruk; Csoka, Antonei B.; Bhatti, Amna; Copeland, Robert L.; Tizabi, Yousef (2020). "Butyrate Protects Against Salsolinol-Induced Toxicity in SH-SY5Y Cells: Implication for Parkinson's Disease". Neurotoxicity Research 38 (3): 596–602. doi:10.1007/s12640-020-00238-5. PMID 32572814. 
  20. ↑ Wang, Yumin; Wu, Shuang; Li, Qiang; Lang, Weihong; Li, Wenjing; Jiang, Xiaodong; Wan, Zhirong; Sun, Huiyan et al. (2022). "Salsolinol Induces Parkinson's Disease Through Activating NLRP3-Dependent Pyroptosis and the Neuroprotective Effect of Acteoside". Neurotoxicity Research 40 (6): 1948–1962. doi:10.1007/s12640-022-00608-1. PMID 36454451. https://link.springer.com/article/10.1007/s12640-022-00608-1. Retrieved 29 January 2024. 
  21. ↑ Lee, Jeongrim; Ramchandani, Vijay A.; Hamazaki, Kei; Engleman, Eric A.; McBride, William J.; Li, Ting-Kai; Kim, Hee-Yong (2010). "A Critical Evaluation of Influence of Ethanol and Diet on Salsolinol Enantiomers in Humans and Rats". Alcoholism: Clinical and Experimental Research 34 (2): 242–250. doi:10.1111/j.1530-0277.2009.01087.x. PMID 19951298. 
  22. ↑ Hipólito, Lucía; Sánchez-Catalán, María José; Martí-Prats, Lucía; Granero, Luis; Polache, Ana (2012). "Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: Old and new vistas". Neuroscience & Biobehavioral Reviews 36 (1): 362–378. doi:10.1016/j.neubiorev.2011.07.007. PMID 21802444. https://www.sciencedirect.com/science/article/pii/S0149763411001424. Retrieved 28 January 2024. 
  23. ↑ "(R)-Salsolinol, a product of ethanol metabolism, stereospecifically induces behavioral sensitization and leads to excessive alcohol intake. | PubFacts.com". https://www.pubfacts.com/detail/26032572/R-Salsolinol-a-product-of-ethanol-metabolism-stereospecifically-induces-behavioral-sensitization-and. 



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