Pinoline

Pinoline
Clinical data
Other names6-Methoxy-THBC; 6-Methoxy-THβC; 6-MeO-THBC; 6-MeO-THβC; 5-MeO-TLN; 6-Methoxytryptoline; 6-Methoxy-2,3,4,9-tetrahydro-1H-β-carboline; 6-Methoxy-1,2,3,4-tetrahydro-β-carboline; 6-Methoxy-tetrahydronorharman; 6-Methoxy-2,3,4,9-tetrahydro-1H-β-carboline; Pineal β-carboline
Drug classSerotonin receptor modulator; Serotonin 5-HT2A receptor agonist; Serotonin 5-HT2C receptor agonist; Serotonin 5-HT2B receptor antagonist; Serotonin reuptake inhibitor
ATC code
  • None
Identifiers
  • 6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.161.873 Edit this at Wikidata
Chemical and physical data
FormulaC12H14N2O
Molar mass202.257 g·mol−1
3D model (JSmol)
Melting point216 to 224 °C (421 to 435 °F)
  • COC1=CC2=C(C=C1)NC3=C2CCNC3
  • InChI=1S/C12H14N2O/c1-15-8-2-3-11-10(6-8)9-4-5-13-7-12(9)14-11/h2-3,6,13-14H,4-5,7H2,1H3 X markN
  • Key:QYMDEOQLJUUNOF-UHFFFAOYSA-N X markN
 X markNcheckY (what is this?)  (verify)

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. Its more common name is a contraction of "pineal β-carboline". The biological activity of this molecule is of interest as a potential free radical scavenger, also known as an antioxidant, and as a monoamine oxidase A inhibitor.

Use and effects

It remains unknown whether pinoline has hallucinogenic effects in humans.

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). 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 EC50Tooltip half-maximal effective concentration (EmaxTooltip maximal efficacy) values of 2,140 nM (75%) at the serotonin 5-HT2A receptor and 33 nM (95%) at the serotonin 5-HT2C receptor and an IC50Tooltip half-maximal inhibitory concentration of 1,120 nM at the serotonin 5-HT2B receptor. Hence, pinoline appears to act as a potent and selective serotonin 5-HT2C receptor agonist.

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

Both pinoline and tryptoline partially substitute for the psychedelic drug LSD in rodent drug discrimination tests. 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). Pinoline has also been reported to produce anxiogenic-like effects in rodents, which theoretically might be mediated by agonism of serotonin 5-HT2C receptors. In addition, it has been reported to produce antidepressant-like effects in rodents.

Other actions

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

Aluminium toxicity causes an increase in lipid peroxidation, with most damage occurring in the brain. A recent review of studies shows pinoline and melatonin to be effective at reducing the lipid peroxidation. Studies included both human and animal subjects. The studies’ results support that pinoline has antioxidant properties.[citation needed]

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[citation needed]. Pinoline was also shown to be more effective than vitamin E at reducing lipopolysaccharide activity in the retina.

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.

Pharmacokinetics

Pinoline is a substrate for CYP2D6.

Chemistry

Synthesis

The chemical synthesis of pinoline has been described.

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.

Research

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

See also

References

  1. ↑ Barker SA, Borjigin J, Lomnicka I, Strassman R (December 2013). "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. doi:10.1002/bmc.2981. hdl:2027.42/101767. PMID 23881860.
  2. ↑ Callaway JC, Gyntber J, Poso A, Airaksinen MM, Vepsäläinen J (1994). "The pictet-spengler reaction and biogenic tryptamines: Formation of tetrahydro-β-carbolines at physiologicalpH". Journal of Heterocyclic Chemistry. 31 (2): 431. doi:10.1002/jhet.5570310231.
  3. ↑ Schiller E, Bartsch H (2003). Free Radicals and Inhalation Pathology: Respiratory System, Mononuclear Phagocyte System, Hypoxia and Reoxygenation, Pneumoconioses, and Other Granulomatoses, Cancer (Google Books, page view). Springer. p. 107. ISBN 978-3-540-00201-7. Retrieved 2009-02-14.
  4. ↑ Airaksinen MM, Huang JT, Ho BT, Taylor D, Walker K (November 1978). "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. 43 (5). Copenh: 375–380. doi:10.1111/j.1600-0773.1978.tb02281.x. PMID 726902.
  5. 1 2 3 4 5 6 7 8 9 de la Fuente Revenga M, Pérez C, Morales-García JA, Alonso-Gil S, Pérez-Castillo A, Caignard DH, et al. (May 2015). "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. doi:10.1021/acschemneuro.5b00041. PMID 25815906.
  6. 1 2 Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, et al. (August 2000). "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. doi:10.1016/s0376-8716(99)00148-9. PMID 10940539.
  7. ↑ Pähkla R, Rägo L, Callaway JJ, Airaksinen MM (March 1997). "Binding of pinoline on the 5-hydroxytryptamine transporter: competitive interaction with [3H] citalopram". Pharmacology & Toxicology. 80 (3): 122–126. doi:10.1111/j.1600-0773.1997.tb00384.x. PMID 9101584.
  8. 1 2 Komulainen H, Tuomisto J, Airaksinen MM, Kari I, Peura P, Pollari L (April 1980). "Tetrahydro-beta-carbolines and corresponding tryptamines: In vitro inhibition of serotonin, dopamine and noradrenaline uptake in rat brain synaptosomes". Acta Pharmacologica et Toxicologica. 46 (4). Copenh: 299–307. doi:10.1111/j.1600-0773.1980.tb02458.x. PMID 7368949.
  9. ↑ Glennon RA, Grella B, Tyacke RJ, Lau A, Westaway J, Hudson AL (February 2004). "Binding of beta-carbolines at imidazoline I2 receptors: a structure-affinity investigation". Bioorganic & Medicinal Chemistry Letters. 14 (4): 999–1002. doi:10.1016/j.bmcl.2003.11.078. PMID 15013009.
  10. ↑ Sparks DL, Buckholtz NS (October 1980). "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. doi:10.1016/0304-3940(80)90236-0. PMID 7052551.
  11. 1 2 Nielsen EB, White FJ, Holohean AM, Callahan PM, Appel JB (November 1982). "Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines". Life Sciences. 31 (22): 2433–2439. doi:10.1016/0024-3205(82)90747-0. PMID 7154844.
  12. ↑ Pähkla R, Kask A, Rägo L (April 2000). "Differential effects of beta-carbolines and antidepressants on rat exploratory activity in the elevated zero-maze". Pharmacology, Biochemistry, and Behavior. 65 (4): 737–742. doi:10.1016/s0091-3057(99)00265-8. PMID 10764931.
  13. ↑ Pähkla R, Harro J, Rägo L (1996). "Behavioural effects of pinoline in the rat forced swimming, open field and elevated plus-maze tests". Pharmacological Research. 34 (1–2): 73–78. doi:10.1006/phrs.1996.0066. PMID 8981559.
  14. ↑ Sewerynek E, Wiktorska JA, Stuss M (December 2011). "6-methoxytryptophol reduces lipopolysaccharide-induced lipid peroxidation in vitro more effectively than melatonin". Journal of Physiology and Pharmacology. 62 (6): 677–683. PMID 22314571.
  15. ↑ Millán-Plano S, Piedrafita E, Miana-Mena FJ, Fuentes-Broto L, Martínez-Ballarín E, López-Pingarrón L, et al. (January 2010). "Melatonin and structurally-related compounds protect synaptosomal membranes from free radical damage". International Journal of Molecular Sciences. 11 (1): 312–328. doi:10.3390/ijms11010312. PMC 2821006. PMID 20162018.
  16. ↑ Jiang XL, Shen HW, Yu AM (March 2009). "Pinoline may be used as a probe for CYP2D6 activity". Drug Metabolism and Disposition. 37 (3): 443–446. doi:10.1124/dmd.108.025056. PMC 2680515. PMID 19095720.
  17. ↑ Yu AM, Idle JR, Herraiz T, Küpfer A, Gonzalez FJ (June 2003). "Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase". Pharmacogenetics. 13 (6): 307–319. 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. ↑ McIsaac WM, Taylor D, Walker KE, Ho BT (April 1972). "6-Methoxy-1,2,3,4-tetrahydro- -carboline--a serotonin elevator". Journal of Neurochemistry. 19 (4): 1203–1206. doi:10.1111/j.1471-4159.1972.tb01441.x. PMID 5063058.
  20. ↑ Ho BT, Taylor D, Askew WE, McIsaac WM (May 1972). "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. 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.