However, β-carbolines with substituents in position 3 reduce the effect of
benzodiazepine on
GABA-A receptors and can therefore have
convulsive,
anxiogenic and memory enhancing effects.[15] Moreover, 3-hydroxymethyl-beta-carboline blocks the sleep-promoting effect of
flurazepam in rodents and - by itself - can decrease sleep in a dose-dependent manner.[16] Another derivative, methyl-β-carboline-3-carboxylate, stimulates learning and memory at low
doses but can promote anxiety and convulsions at high doses.[15] With modification in position 9 similar positive effects have been observed for learning and memory without promotion of anxiety or convulsion.[12]
β-carboline derivatives also enhance the production of the
antibiotic reveromycin A in soil dwelling "
Streptomyces" species.[17][18] Specifically, expression of
biosyntheticgenes is facilitated by binding of the β-carboline to a large
ATP-binding regulator of the
LuxR family.
Since β-carbolines also interact with various
cancer-related molecules such as
DNA,
enzymes (
GPX4,
kinases, etc.) and
proteins (
ABCG2/BRCP1, etc.), they are also discussed as potential anticancer agents.[3]
Explorative human studies for the medical use of β-carbolines
The extract of the
lianaBanisteriopsis caapi has been used by the tribes of the
Amazon as an
entheogen and was described as a
hallucinogen in the middle of the 19th century.[20] In early 20th century, European pharmacists identified
harmine as the active substance.[21] This discovery stimulated the interest to further investigate its potential as a medicine. For example,
Louis Lewin, a prominent pharmacologist, demonstrated a dramatic benefit in neurological impairments after injections of B. caapi in patients with
postencephalitic Parkinsonism.[20] By 1930, it was generally agreed that
hypokinesia,
drooling, mood, and sometimes rigidity improved by treatment with harmine. Altogether, 25 studies had been published in the 1920s and 1930s about patients with
Parkinson's disease and postencephalitic Parkinsonism. The pharmacological effects of harmine have been attributed mainly to its central
monoamine oxidase (MAO) inhibitory properties.
In-vivo and rodent studies have shown that extracts of Banisteriopsis caapi and also Peganum harmala lead to
striataldopamine release.[22][23][24] Furthermore, harmine supports the survival of dopaminergic neurons in
MPTP-treated mice.[25] Since harmine also
antagonizesN-methyl-d-aspartate (NMDA) receptors,[26] some researchers speculatively attributed the rapid improvement in patients with Parkinson's disease to these antiglutamatergic effects.[20] However, the advent of synthetic
anticholinergic drugs at that time led to the total abandonment of harmine.[20]
Structure
β-Carbolines belong to the group of
indole alkaloids and consist of
a pyridine ring that is fused to an
indole skeleton.[27] The structure of β-carboline is similar to that of
tryptamine, with the
ethylamine chain re-connected to the
indole ring via an extra
carbon atom, to produce a three-ringed structure. The biosynthesis of β-carbolines is believed to follow this route from analogous tryptamines.[28] Different levels of
saturation are possible in the third ring which is indicated here in the
structural formula by coloring the optionally double bonds red and blue:
Examples of β-carbolines
Some of the more important β-carbolines are tabulated by structure below. Their structures may contain the aforementioned bonds marked by red or blue.
The fully
aromatic β-carbolines also occur in many foodstuffs, however in lower concentrations. The highest amounts have been detected in brewed coffee, raisins, well done fish and meats.[35] Smoking is another source of fully aromatic β-carbolines with levels up to thousands of µg per smoker each day.[36]
^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.
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^López-Muñoz F, Alamo C (2009-05-01). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current Pharmaceutical Design. 15 (14): 1563–1586.
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PMID19442174.
^Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G (March 2008). "9-Methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture". Neurochemistry International. 52 (4–5): 688–700.
doi:
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PMID17913302.
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^Polanski W, Reichmann H, Gille G (June 2011). "Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?". Expert Review of Neurotherapeutics. 11 (6): 845–860.
doi:
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^Foley P (2003). "Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism". Wurzburger Medizinhistorische Mitteilungen. 22: 215–234.
PMID15641199.
^Schwarz MJ, Houghton PJ, Rose S, Jenner P, Lees AD (June 2003). "Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism". Pharmacology, Biochemistry, and Behavior. 75 (3): 627–633.
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^Brierley DI, Davidson C (January 2013). "Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell". Journal of Psychopharmacology. 27 (1): 98–108.
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^Hemmateenejad B, Abbaspour A, Maghami H, Miri R, Panjehshahin MR (August 2006). "Partial least squares-based multivariate spectral calibration method for simultaneous determination of beta-carboline derivatives in Peganum harmala seed extracts". Analytica Chimica Acta. 575 (2): 290–299.
Bibcode:
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PMID17723604.
^Herraiz T, González D, Ancín-Azpilicueta C, Arán VJ, Guillén H (March 2010). "beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)". Food and Chemical Toxicology. 48 (3): 839–845.
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^Lake RJ, Blunt JW, Munro MH (1989). "Eudistomins from the New Zealand ascidian Ritterella sigillinoides". Aust. J. Chem. 42 (7): 1201–1206.
doi:
10.1071/CH9891201.
^Badre A, Boulanger A, Abou-Mansour E, Banaigs B, Combaut G, Francisco C (April 1994). "Eudistomin U and isoeudistomin U, new alkaloids from the Caribbean ascidian Lissoclinum fragile". Journal of Natural Products. 57 (4): 528–533.
doi:
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PMID8021654.
^Davis RA, Carroll AR, Quinn RJ (July 1998). "Eudistomin V, a new beta-carboline from the Australian ascidian Pseudodistoma aureum". Journal of Natural Products. 61 (7): 959–960.
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^Becher PG, Beuchat J, Gademann K, Jüttner F (December 2005). "Nostocarboline: isolation and synthesis of a new cholinesterase inhibitor from Nostoc 78-12A". Journal of Natural Products. 68 (12): 1793–1795.
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