β-Carboline

The pharmacological effects of specific β-carbolines are dependent on their substituents. For example, the natural β-carboline harmine has substituents on position 7 and 1. Thereby, it acts as a selective inhibitor of the DYRK1A protein kinase, a molecule necessary for neurodevelopment.[4][5] It also exhibits various antidepressant-like effects in rats by interacting with serotonin receptor 2A.[6][7] Furthermore, it increases levels of the brain-derived neurotrophic factor (BDNF) in rat hippocampus.[7][8] A decreased BDNF level has been associated with major depression in humans. The antidepressant effect of harmine might also be due to its function as a MAO-A inhibitor by reducing the breakdown of serotonin and noradrenaline.[8][9]

A synthetic derivative, 9-methyl-β-carboline, has shown neuroprotective effects including increased expression of neurotrophic factors and enhanced respiratory chain activity.[10][11] This derivative has also been shown to enhance cognitive function,[12] increase dopaminergic neuron count and facilitate synaptic and dendritic proliferation.[13][14] It also exhibited therapeutic effects in animal models for Parkinson's disease and other neurodegenerative processes.[11]

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 biosynthetic genes is facilitated by binding of the β-carboline to a large ATP-binding regulator of the LuxR family.

Also Lactobacillus spp. secretes a β-carboline (1-acetyl-β-carboline) preventing the pathogenic fungus Candida albicans to change to a more virulent growth form (yeast-to-filament transition). Thereby, β-carboline reverses imbalances in the microbiome composition causing pathologies ranging from vaginal candidiasis to fungal sepsis.[19]

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]

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:

Substituted beta-carbolines (structural formula)

Some of the more important β-carbolines are tabulated by structure below. Their structures may contain the aforementioned bonds marked by red or blue.

Short Name	R1	R6	R7	R9	Structure
β-Carboline	H	H	H	H
Pinoline	H	OCH3	H	H
Harmane	CH3	H	H	H
Harmine	CH3	H	OCH3	H
Harmaline	CH3	H	OCH3	H
Harmalol	CH3	H	OH	H
Tetrahydroharmine	CH3	H	OCH3	H
9-Methyl-β-carboline	H	H	H	CH3
3-Carboxy-Tetrahydrononharman	H / CH3 / COOH	H	H	H

A Paruroctonus scorpion fluorescing under a blacklight

β-Carboline alkaloids are widespread in prokaryotes, plants and animals. Some β-carbolines, notably tetrahydro-β-carbolines, may be formed naturally in plants and the human body with tryptophan, serotonin and tryptamine as precursors.

• Altogether, eight plant families are known to express 64 different kinds of β-carboline alkaloids. For example, the β-carbolines harmine, harmaline, and tetrahydroharmine are components of the liana Banisteriopsis caapi and play a pivotal role in the pharmacology of the indigenous psychedelic drug ayahuasca. Moreover, the seeds of Peganum harmala (Syrian Rue) contain between 0.16%[29] and 5.9%[30] β-carboline alkaloids (by dry weight).
• A specific group of β-carboline derivatives, termed eudistomins, were extracted from ascidians (marine tunicates of the family Ascidiacea) such as Ritterella sigillinoides,[31] Lissoclinum fragile [32] or Pseudodistoma aureum.[33]
• Nostocarboline was isolated from freshwater cyanobacterium.[34]
• 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]
• β-Carbolines have also been found in the cuticle of scorpions, causing their skin to fluoresce upon exposed to ultraviolet light at certain wavelengths (e.g. blacklight).[37]

• Gamma-carboline
• Harmala alkaloid
• Oxopropaline[38]
• Tryptamine

• Beta-Carbolines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• TiHKAL #44
• TiHKAL in general
• Beta-carbolines in coffee
• 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. PMID 16183262. S2CID 54410407.