However, β-carbolines with substituents in position 3 reduce the effect ofbenzodiazepine onGABA-A receptors and can therefore haveconvulsive,anxiogenic and memory enhancing effects.[15] Moreover, 3-hydroxymethyl-beta-carboline blocks the sleep-promoting effect offlurazepam 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 lowdoses 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 theantibiotic reveromycin A in soil-dwellingStreptomyces species.[17][18] Specifically, expression ofbiosyntheticgenes is facilitated by binding of the β-carboline to a largeATP-binding regulator of theLuxR family.
Since β-carbolines also interact with variouscancer-related molecules such asDNA,enzymes (GPX4,kinases, etc.) andproteins (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 thelianaBanisteriopsis caapi has been used by the tribes of theAmazon as anentheogen and was described as ahallucinogen in the middle of the 19th century.[20] In early 20th century, European pharmacists identifiedharmine 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 ofB. caapi in patients withpostencephalitic Parkinsonism.[20] By 1930, it was generally agreed thathypokinesia,drooling, mood, and sometimes rigidity improved by treatment with harmine. Altogether, 25 studies had been published in the 1920s and 1930s about patients withParkinson's disease and postencephalitic Parkinsonism. The pharmacological effects of harmine have been attributed mainly to its centralmonoamine oxidase (MAO) inhibitory properties.In-vivo and rodent studies have shown that extracts ofBanisteriopsis caapi and alsoPeganum harmala lead tostriataldopamine release.[22][23][24] Furthermore, harmine supports the survival of dopaminergic neurons inMPTP-treated mice.[25] Since harmine alsoantagonizesN-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 syntheticanticholinergic drugs at that time led to the total abandonment of harmine.[20]
β-Carbolines belong to the group ofindole alkaloids and consist ofa pyridine ring that is fused to anindole skeleton.[27] The structure of β-carboline is similar to that oftryptamine, with theethylamine chain re-connected to theindole ring via an extracarbon atom, to produce a three-ringed structure. The biosynthesis of β-carbolines is believed to follow this route from analogous tryptamines.[28] Different levels ofsaturation are possible in the third ring which is indicated here in thestructural formula by coloring the optionally double bonds red and blue:
The fullyaromatic 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]
^Francik R, Kazek G, Cegła M, Stepniewski M (March 2011). "Antioxidant activity of beta-carboline derivatives".Acta Poloniae Pharmaceutica.68 (2):185–189.PMID21485291.
^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.PMID10940539.
^abFortunato JJ, Réus GZ, Kirsch TR, Stringari RB, Fries GR, Kapczinski F, et al. (October 2010). "Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus".Journal of Neural Transmission.117 (10):1131–1137.doi:10.1007/s00702-010-0451-2.PMID20686906.S2CID21595062.
^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.doi:10.2174/138161209788168001.PMID19442174.
^abWernicke C, Hellmann J, Zieba B, Kuter K, Ossowska K, Frenzel M, et al. (January 2010). "9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease".Pharmacological Reports.62 (1):35–53.doi:10.1016/s1734-1140(10)70241-3.PMID20360614.S2CID16729205.
^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:10.1016/j.neuint.2007.08.018.PMID17913302.S2CID24226033.
^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:10.1586/ern.11.1.PMID21651332.S2CID24899640.
^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.doi:10.1016/s0091-3057(03)00129-1.PMID12895680.S2CID28243440.
^Brierley DI, Davidson C (January 2013). "Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell".Journal of Psychopharmacology.27 (1):98–108.doi:10.1177/0269881112463125.PMID23076833.S2CID40115950.
^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:2006AcAC..575..290H.doi:10.1016/j.aca.2006.05.093.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.doi:10.1016/j.fct.2009.12.019.hdl:10261/77694.PMID20036304.
^Lake RJ, Blunt JW, Munro MH (1989). "Eudistomins from the New Zealand ascidianRitterella 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:10.1021/np50106a016.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.doi:10.1021/np9800452.PMID9677285.
^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.doi:10.1021/np050312l.PMID16378379.
Farzin D, Mansouri N (July 2006). "Antidepressant-like effect of harmane and other beta-carbolines in the mouse forced swim test".European Neuropsychopharmacology.16 (5):324–328.doi:10.1016/j.euroneuro.2005.08.005.PMID16183262.S2CID54410407.
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