9-Methyl-β-carboline
   HOME

TheInfoList



OR:

9-Methyl-β-carboline (9-Me-BC) is a heterocyclic amine of the β-carboline family, and a
research chemical Research chemicals are chemical substances which scientists use for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human ...
sometimes used as a
nootropic Nootropics ( or ) (colloquially brain supplements, smart drugs, cognitive enhancers, memory enhancers, or brain boosters) are chemical substances which purportedly improve cognitive functions, such as attention, memory, wakefulness, and self ...
. It is a
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...
, primarily of MAO-A. In mice studies, it has been found to stimulate the growth of dopaminergic neurons and increase gene expression of several
neurotrophic factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...
s in both dopamine-depleted and normal brain cultures. It has been proposed for further investigation in the treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
.


Chemistry

9-Me-BC is a
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
ated
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
of β-carboline with the molecular formula C12H10N2. It may be prepared by performing the Eschweiler–Clarke reaction on freebase β-carboline (norharmane)


Biological effects

''
In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' studies with
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
rgic
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
cell cultures demonstrated increased expression of
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
and associated
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
, increased neurite outgrowth, regeneration of neurons after chronic
rotenone Rotenone is an odorless, colorless, crystalline isoflavone. It occurs naturally in the seeds and stems of several plants, such as the jicama vine, and in the roots of several other members of the Fabaceae. It was the first-described member of the ...
administration, and reduced expression of inflammatory
cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
. 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. 9-Me-BC also inhibited the oxidation of the neurotoxin precursor MPTP to the dopaminergic neurotoxin MPP+ ''in vitro'' and displayed protective effects against the neurotoxin 2,9-DiMe-BC+ (2,9-dimethyl-β-carbolinium); although there are concerns about its chemical similarity to 9-Me-BC itself. These findings suggest that it could potentially defend against other dopaminergic
neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...
s as well. The administration of the dopamine antagonist
sulpiride Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic) medication of the benzamide class which is used mainly in the treatment of psychosi ...
which antagonizes D2 and D3 receptors did not have a significant effect on the observed increase of dopaminergic TH+ neurons after treatment with the chemical, suggesting that the neurostimulative effect of 9-Me-BC functions independently of these two receptors. When the by which 9-Me-BC is taken up into and subsequently enters the neuron through is blocked, the observed proliferation of dopaminergic neurons was abolished, but neurite outgrowth was not. This leads to the hypothesis that the neurite outgrowth perhaps functions through a separate mechanism such as through the uptake of 9-Me-BC into dopaminergic
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
cells via an organic cation transporter (OCT), rather than the DAT. The former result further substantiates that 9-Me-BC is indeed a substrate for the dopamine transporter. Rodent studies ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' demonstrated elevated hippocampal
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
levels, improved spatial learning performance in a radial maze test, and increased
dendrite A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...
outgrowth in the
dentate gyrus The dentate gyrus (DG) is one of the subfields of the hippocampus, in the hippocampal formation. The hippocampal formation is located in the temporal lobe of the brain, and includes the hippocampus (including CA1 to CA4) subfields, and other su ...
of the hippocampus, as well as restoration of the number of tyrosine hydroxylase expressing neurons in the left
striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...
after an injection of MPP+ had reduced the number of such cells by 50% in an animal model of
Parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...
. In in-vitro murine
midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...
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
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s taken from mice, it significantly increased the gene expression of
brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...
(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. 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. 9-Me-BC may possess photosensitizing effects.


Pharmacological effects

9-Me-BC is a known
inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...
of
monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...
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.


See also

*
Substituted β-carboline A substituted β-carboline is a chemical compound featuring a β-carboline moiety (chemistry), moiety with one or more chemical substituent, substitutions. β-Carbolines include more than one hundred alkaloids and synthetic compounds. The effect ...
* Harmane * Gacyclidine


References

{{DEFAULTSORT:Methyl-β-carboline, 9- 1-Alkyltryptamines Beta-Carbolines N-Monoalkyltryptamines Monoamine oxidase inhibitors Experimental drugs Methyl compounds Nootropics