Chemistry:Pinoline

From HandWiki

Pinoline, also known as 6-methoxytryptoline or as 6-methoxy-1,2,3,4-tetrahydro-β-carboline (6-MeO-THβC), is a β-carboline long-claimed to be produced in the pineal gland during the metabolism of melatonin, however its pineal occurrence remains controversial.[1] Its more common name is a contraction of "pineal β-carboline".[2] The biological activity of this molecule is of interest as a potential free radical scavenger, also known as an antioxidant,[3] and as a monoamine oxidase A inhibitor.[4]

Use and effects

It remains unknown whether pinoline has hallucinogenic effects in humans.[5]

Pharmacology

Pharmacodynamics

Pinoline shows affinity for serotonin receptors, including the serotonin 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors (Ki = 156–4,335 nM).[5][6] It is a high-efficacy partial agonist of the serotonin 5-HT2A receptor, an antagonist of the serotonin 5-HT2B receptor, and a full agonist of the serotonin 5-HT2C receptor, with EC50 (Emax) values of 2,140 nM (75%) at the serotonin 5-HT2A receptor and 33 nM (95%) at the serotonin 5-HT2C receptor and an IC50 of 1,120 nM at the serotonin 5-HT2B receptor.[5] Hence, pinoline appears to act as a potent and selective serotonin 5-HT2C receptor agonist.[5]

The drug shows affinity for the serotonin transporter (SERT) (Ki = 172–572 nM).[5][7][8] It is a serotonin reuptake inhibitor, with an IC50 value of 1,100 nM.[8] Pinoline shows affinity for the imidazoline I2 receptor (Ki = 1,640 nM) and for the α2-adrenergic receptor (Ki = 7,830 nM).[9] Conversely, it shows no affinity for the dopamine D2 receptor (Ki = >10,000 nM).[6] The drug is a weak monoamine oxidase inhibitor (MAOI), with an IC50 value for inhibition of MAO-A of 41,500 nM.[5][10]

Both pinoline and tryptoline partially substitute for the psychedelic drug LSD in rodent drug discrimination tests.[11] The substitution by tryptoline was further assessed and was found to be blocked by the serotonin receptor antagonist pizotifen and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA).[11] Pinoline has also been reported to produce anxiogenic-like effects in rodents, which theoretically might be mediated by agonism of serotonin 5-HT2C receptors.[5][12] In addition, it has been reported to produce antidepressant-like effects in rodents.[13]

Other actions

One of pinoline's pharmacological properties is its ability to promote neurogenesis in vitro; even at trace concentrations.[5]


Lipopolysaccharide is produced by Gram-negative bacteria and stimulates the production of free radicals which in turn cause lipid peroxidation. A recent study compared the effectiveness of melatonin and other similar compounds on the lipopolysaccharide induced lipid peroxidation. The results showed support for pinoline’s ability to reduce damage from lipid peroxidation . Pinoline was also shown to be more effective than vitamin E at reducing lipopolysaccharide activity in the retina.[14]

A 2010 study compared the antioxidant properties of compounds from the tryptophan metabolic pathway in the pineal gland against oxidative damage to the lipids and proteins of synaptosomes. Synaptosomes isolated from rat brains were used in an experiment assessing damage by measuring malondialdehyde, 4-hydroxyalkenal, and carbonyl content in the proteins. Pinoline was shown to be the most powerful antioxidant. These results support the evidence for pinoline’s antioxidant abilities and the potential to protect against oxidative damage.[15]

Pharmacokinetics

Pinoline is a substrate for CYP2D6.[16][17]

Chemistry

Synthesis

The chemical synthesis of pinoline has been described.[5]

Analogues

Analogues of pinoline include tryptoline, 6-MeO-THH, shepherdine, 1-ethyl-6-hydroxytryptoline, tetrahydroharmine (THH or 7-MeO-THH), and tetrahydroharmol, among others.

History

Pinoline was first described int he scientific literature by at least 1969.[18][19][20]

Research

Bausch & Lomb filed a patent for a drug delivery device utilizing this molecule, designed to treat various ophthalmic disorders in 2006.[21]

See also

References

  1. ↑ "LC/MS/MS analysis of the endogenous dimethyltryptamine hallucinogens, their precursors, and major metabolites in rat pineal gland microdialysate". Biomedical Chromatography 27 (12): 1690–1700. December 2013. doi:10.1002/bmc.2981. PMID 23881860. 
  2. ↑ "The pictet-spengler reaction and biogenic tryptamines: Formation of tetrahydro-β-carbolines at physiologicalpH". Journal of Heterocyclic Chemistry 31 (2): 431. 1994. doi:10.1002/jhet.5570310231. 
  3. ↑ (Google Books, page view) Free Radicals and Inhalation Pathology: Respiratory System, Mononuclear Phagocyte System, Hypoxia and Reoxygenation, Pneumoconioses, and Other Granulomatoses, Cancer. Springer. 2003. p. 107. ISBN 978-3-540-00201-7. https://books.google.com/books?id=y5aQMpT6tC0C. Retrieved 2009-02-14. 
  4. ↑ "The uptake of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline and its effect on 5-hydroxytryptamine uptake and release in blood platelets". Acta Pharmacologica et Toxicologica (Copenh) 43 (5): 375–380. November 1978. doi:10.1111/j.1600-0773.1978.tb02281.x. PMID 726902. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin-Pinoline Hybrids". ACS Chemical Neuroscience 6 (5): 800–810. May 2015. doi:10.1021/acschemneuro.5b00041. PMID 25815906. 
  6. ↑ 6.0 6.1 "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors". Drug and Alcohol Dependence 60 (2): 121–132. August 2000. doi:10.1016/s0376-8716(99)00148-9. PMID 10940539. 
  7. ↑ "Binding of pinoline on the 5-hydroxytryptamine transporter: competitive interaction with [3H] citalopram". Pharmacology & Toxicology 80 (3): 122–126. March 1997. doi:10.1111/j.1600-0773.1997.tb00384.x. PMID 9101584. 
  8. ↑ 8.0 8.1 "Tetrahydro-beta-carbolines and corresponding tryptamines: In vitro inhibition of serotonin, dopamine and noradrenaline uptake in rat brain synaptosomes". Acta Pharmacologica et Toxicologica (Copenh) 46 (4): 299–307. April 1980. doi:10.1111/j.1600-0773.1980.tb02458.x. PMID 7368949. 
  9. ↑ "Binding of beta-carbolines at imidazoline I2 receptors: a structure-affinity investigation". Bioorganic & Medicinal Chemistry Letters 14 (4): 999–1002. February 2004. doi:10.1016/j.bmcl.2003.11.078. PMID 15013009. 
  10. ↑ "6-Methoxy-1,2,3,4-tetrahydro-beta-carboline: a specific monoamine oxidase-A inhibitor in CF-1 mouse brain". Neuroscience Letters 20 (1): 73–78. October 1980. doi:10.1016/0304-3940(80)90236-0. PMID 7052551. 
  11. ↑ 11.0 11.1 "Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines". Life Sciences 31 (22): 2433–2439. November 1982. doi:10.1016/0024-3205(82)90747-0. PMID 7154844. 
  12. ↑ "Differential effects of beta-carbolines and antidepressants on rat exploratory activity in the elevated zero-maze". Pharmacology, Biochemistry, and Behavior 65 (4): 737–742. April 2000. doi:10.1016/s0091-3057(99)00265-8. PMID 10764931. 
  13. ↑ "Behavioural effects of pinoline in the rat forced swimming, open field and elevated plus-maze tests". Pharmacological Research 34 (1–2): 73–78. 1996. doi:10.1006/phrs.1996.0066. PMID 8981559. 
  14. ↑ "6-methoxytryptophol reduces lipopolysaccharide-induced lipid peroxidation in vitro more effectively than melatonin". Journal of Physiology and Pharmacology 62 (6): 677–683. December 2011. PMID 22314571. 
  15. ↑ "Melatonin and structurally-related compounds protect synaptosomal membranes from free radical damage". International Journal of Molecular Sciences 11 (1): 312–328. January 2010. doi:10.3390/ijms11010312. PMID 20162018. 
  16. ↑ "Pinoline may be used as a probe for CYP2D6 activity". Drug Metabolism and Disposition 37 (3): 443–446. March 2009. doi:10.1124/dmd.108.025056. PMID 19095720. 
  17. ↑ "Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase". Pharmacogenetics 13 (6): 307–319. June 2003. doi:10.1097/01.fpc.0000054094.48725.b7. PMID 12777961. 
  18. ↑ Taylor, D. P. (1969). Metabolism of 6-methoxy 1, 2, 3, 4 tetrahydro-[beta]-carboline: a specific serotonin elevator (Doctoral dissertation, University of Texas Health Science Center at Houston. Graduate School of Biomedical Sciences.).
  19. ↑ "6-Methoxy-1,2,3,4-tetrahydro- -carboline--a serotonin elevator". Journal of Neurochemistry 19 (4): 1203–1206. April 1972. doi:10.1111/j.1471-4159.1972.tb01441.x. PMID 5063058. 
  20. ↑ "Effects of 6-methoxy-1,2,3,4-tetrahydro- -carboline on the regional and subcellular distribution of serotonin in mouse and rat brains". Life Sciences. Pt. 1 11 (10): 493–502. May 1972. doi:10.1016/0024-3205(72)90199-3. PMID 4540330. 
  21. ↑ Bartels, S. P. (2006) U.S. Patent No. 20,060,292,202 Washington, DC: U.S.



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Pinoline&oldid=4646067"