9-Methyl-β-carboline

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Contents

9-Methyl-β-carboline
9-Me-BC bkchem autocropped.svg
9-Me-b-carboline 3D BS.png
Names
Preferred IUPAC name
5-Methyl-5H-pyrido[3,4-b]indole
Other names
  • 9-Me-BC
  • 9-Methyl-9H-β-carboline
  • 9-Methylnorharman
  • 9-MBC
  • N-Methyl-β-carboline
Identifiers
3D model (JSmol)
ChemSpider
MeSH C529608
PubChem CID
UNII
  • InChI=1S/C12H10N2/c1-14-11-5-3-2-4-9(11)10-6-7-13-8-12(10)14/h2-8H,1H3
    Key: MABOIYXDALNSES-UHFFFAOYSA-N
  • CN1C2=CC=CC=C2C3=C1C=NC=C3
Properties
C12H10N2
Molar mass 182.226 g·mol−1
AppearanceWhite, off-white, or tan powder
Pharmacology
Oral, sublingual, intranasal
Legal status
  • In general: legal
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

9-Methyl-β-carboline (9-Me-BC) is a heterocyclic amine of the β-carboline family, and a research chemical [1] sometimes used as a nootropic. It is a monoamine oxidase inhibitor, primarily of MAO-A. [2]

In animal studies, it has been found to stimulate the growth of dopaminergic neurons and increase gene expression of several neurotrophic factors in the brain of both dopamine-depleted and normal cultures. [2]

It has been proposed for further investigation in the treatment of Parkinson's disease. [3]

Chemistry

9-Me-BC is a methylated derivative of β-carboline with the molecular formula C12H10N2.

It may be prepared by performing the Eschweiler–Clarke reaction on freebase β-carboline (norharmane) [ citation needed ]

Biological effects

In vitro studies with dopaminergic neuron cell cultures demonstrated increased expression of tyrosine hydroxylase and associated transcription factors, increased neurite outgrowth, regeneration of neurons after chronic rotenone administration, and reduced expression of inflammatory cytokines. [1] In studies of primary mesencephalic dopaminergic neuron cell cultures, the substance increased the number of differentiated dopaminergic neurons and produced higher levels of transcription factors associated with dopaminergic differentiation. [4]

9-Me-BC also inhibited the oxidation of the neurotoxin precursor MPTP to the dopaminergic neurotoxin MPP+ in vitro [5] and displayed protective effects against the related neurotoxin 2,9-DiMe-BC+ (2,9-dimethyl-ß-carbolinium), [1] suggesting that it could potentially protect against other dopaminergic neurotoxins that share the same mechanism of toxicity.

The administration of the dopamine antagonist sulpiride which antagonizes D2 and D3 receptors did not have a signficant effect on the observed increase of TH+ neurons after treatment with 9-Me-BC, suggesting that its neurostimulative effect is independent of these receptors. [2] When the dopamine transporter (DAT) by which 9-Me-BC is taken up into and subsequently enters the neuron through is blocked, the increase in dopaminergic neurons was abolished, but neurite outgrowth was not. [1] This leads to the hypothesis that the latter is perhaps dependent on the substance's uptake into dopaminergic astrocyte cells via an organic cation transporter (OCT), [2] while the former results substantiates 9-Me-BC being a substrate for the DAT.

Rodent studies in vivo demonstrated elevated hippocampal dopamine levels, improved spatial learning performance in a radial maze test, and increased dendrite outgrowth in the dentate gyrus of the hippocampus, [6] as well as restoration of the number of tyrosine hydroxylase expressing neurons in the left striatum after an injection of MPP+ had reduced the number of such cells by 50% in an animal model of Parkinsonism. [7]

In in-vitro murine midbrain cell cultures, a maximum 33% increase in the number of dopaminergic tyrosine hydroxylase neurons (TH+) after 48 hours of treatment with 9-Me-BC was observed. These effects were found at 90 µM of 9-Me-BC, while higher concentrations of 125 µM and 150 µM progressively decreased the number of dopaminergic neurons.

In cortical dopaminergic astrocytes taken from mice, it significantly increased the gene expression of brain-derived neurotrophic factor (BDNF) by 2-fold. The study also found an increase in the expression of NCAM1, TGF-β2, Skp1, neurotrophin 3, and artemin factors by 1.4-fold, 1.4-fold, 1.5-fold, 1.8-fold, and 3.2-fold respectively. [2] Skp1 may increase the turnover rate of the α-synuclein protein, whose accumulation is associated with Parkinson's disease.

Administration of LY-294002, an inhibitor of the Pi3K/Akt pathway, completely blocked the neurostimulative properties of 9-Me-BC to TH+ neurons, implying that this pathway is critical to its effect on neuronal growth. [2]

9-Me-BC may possess photosensitizing effects. [8]

Pharmacological effects

9-Me-BC is a known inhibitor of monoamine oxidase A and monoamine oxidase B, with IC50 values of 1 µM for MAO-A and 15.5 µM for MAO-B, suggesting that it is more selective for MAO-A like other beta-carbolines. [2]

See also

References

  1. 1 2 3 4 Polanski W, Enzensperger C, Reichmann H, Gille G (2010). "The exceptional properties of 9-methyl-β-carboline: Stimulation, protection and regeneration of dopaminergic neurons coupled with anti-inflammatory effects". J Neurochem. 113 (6): 1659–1675. doi: 10.1111/j.1471-4159.2010.06725.x . PMID   20374418.
  2. 1 2 3 4 5 6 7 Gille G, Hermann A, Reichmann H, Enzersperger C, Polanski W, Keller S (2020). "9-Methyl-β-carboline inhibits monoamine oxidase activity and stimulates the expression of neurotrophic factors by astrocytes". Journal of Neural Transmission. 127 (7): 999–1012. doi: 10.1007/s00702-020-02189-9 . PMID   32285253.
  3. ↑ Polanski W, Reichmann H, Gille G (2011). "Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?". Expert Rev Neurother. 11 (6): 845–860. doi:10.1586/ern.11.1. PMID   21651332. S2CID   24899640.
  4. ↑ Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G (2008). "9-Methyl-β-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture". Neurochem. Int. 52 (4–5): 688–700. doi:10.1016/j.neuint.2007.08.018. PMID   17913302. S2CID   24226033.
  5. ↑ Herraiz T, Guillén H (2011). "Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors". Food Chem. Toxicol. 49 (8): 1773–1781. doi:10.1016/j.fct.2011.04.026. hdl:10261/63126. PMID   21554916.
  6. ↑ Gruss M, Appenroth D, Flubacher A, Enzersperger C, Bock J, Fleck C, Gille G, Braun K (2012). "9-Methyl-β-carboline-induced cognitive enhancement is associated with elevated hippocampal dopamine levels and dendritic and synaptic proliferation". J Neurochem. 121 (6): 924–931. doi: 10.1111/j.1471-4159.2012.07713.x . PMID   22380576.
  7. ↑ Wernicke C, Hellmann J, Zieba B, Kuter K, Ossowska K, Frenzel M, Bencher NA, Rommelspacher H (2010). "9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease". Pharmacol Rep. 62 (1): 35–53. doi:10.1016/s1734-1140(10)70241-3. PMID   20360614. S2CID   16729205.
  8. ↑ Vignoni M, Rasse-Suriani FA, Butzbach K, Erra-Balsells R, Epe B, Cabrerizo FM (2013). "Mechanisms of DNA damage by photoexcited 9-methyl-β-carbolines". Org Biomol Chem. 11 (32): 5300–9. doi:10.1039/c3ob40344k. hdl: 11336/2178 . PMID   23842892.
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