Substituted β-carboline

thumb|right|200px|class=skin-invert-image|The [[chemical structure of β-carboline, the parent compound of the β-carbolines.]]

A substituted β-carboline, also known as a substituted 9H-pyrido[3,4-b]indole, is a chemical compound featuring a β-carboline moiety with one or more substitutions. β-Carbolines include more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines primarily influence brain functions but can also exhibit antioxidant effects. Synthetically designed β-carboline derivatives have recently been shown to have neuroprotective, cognitive enhancing and anti-cancer properties.

β-Carbolines are indole alkaloids featuring a fused pyridine and indole ring structure similar to tryptamine, forming a three-ringed system with variable saturation in the third ring. β-Carboline alkaloids naturally occur widely in prokaryotes, plants, animals, certain marine tunicates, and foods like coffee and smoked meats, and are also responsible for the fluorescence of scorpion cuticles under ultraviolet light. β-Carbolines occurring naturally in Peganum harmala (Syrian rue) are known as harmala alkaloids. According to Alexander Shulgin, harmaline is the only β-carboline that has been extensively studied and well-established as a hallucinogen. Some simple β-carbolines have been reported to be hallucinogenic and have been referred to as oneirogens. Although structurally related to psychedelic tryptamines, the hallucinogenic effects of β-carbolines are said to be qualitatively distinct from those of serotonergic psychedelics. Instead, they are described as being similar to those of ibogaine, which is also a cyclized tryptamine and structurally related atypical hallucinogen.

As monoamine oxidase inhibitors

Various β-carbolines are potent monoamine oxidase inhibitors (MAOIs), more specifically reversible inhibitors of MAO-A (RIMAs). They can also used in a similar fashion with 5-MeO-DMT. It also exhibits various antidepressant-like effects in rats by interacting with serotonin receptor 2A. Furthermore, it increases levels of the brain-derived neurotrophic factor (BDNF) in rat hippocampus. 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.

A synthetic derivative, 9-methyl-β-carboline, has shown neuroprotective effects including increased expression of neurotrophic factors and enhanced respiratory chain activity. This derivative has also been shown to enhance cognitive function, increase dopaminergic neuron count and facilitate synaptic and dendritic proliferation. It also exhibited therapeutic effects in animal models for Parkinson's disease and other neurodegenerative processes. 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. Another derivative, methyl-β-carboline-3-carboxylate, stimulates learning and memory at low doses but can promote anxiety and convulsions at high doses. 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.

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. Findings are conflicting on whether serotonin 5-HT2A receptor activation may be involved or not. β-Carbolines and ibogaine show stimulus generalization with serotonergic psychedelics like DOM and LSD in rodent drug discrimination tests and this generalization can be blocked by serotonin 5-HT2 receptor antagonists.

Although traditional β-carbolines and harmala alkaloids are inactive as serotonin 5-HT2A receptor agonists and do not act as serotonergic psychedelics, certain synthetic tryptoline derivatives, such as 1-ethyl-6-hydroxytryptoline and 1-(2,4,5-trimethoxyphenyl)-6-chlorotryptoline, have more recently been found to be potent and high-efficacy serotonin 5-HT2A and 5-HT2C receptor agonists. In early 20th century, European pharmacists identified harmine as the active substance. 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. Furthermore, harmine supports the survival of dopaminergic neurons in MPTP-treated mice. Since harmine also antagonizes N-methyl-d-aspartate (NMDA) receptors, some researchers speculatively attributed the rapid improvement in patients with Parkinson's disease to these antiglutamatergic effects. 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. 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:

Overview of simple β-carbolines

{| class="wikitable"

! Indole sub. !! Aromatic (H0) !! Dihydro (H2) !! Tetrahydro (H4) !! Tryptamine counterpart

! colspan="5" | with a 1-methyl substituent

| Ar-H || Harman || Harmalan || Tetrahydroharman || Tryptamine

| Ar-5-OH || 5-Harmol || 5-Harmalol || 5-Tetrahydroharmol || 4-Hydroxytryptamine

| Ar-5-OMe || 5-Methoxyharman || 5-Methoxyharmalan || 5-MeO-THH || 4-Methoxytryptamine

| Ar-6-OH || 6-Harmol || 6-Harmalol || 6-Tetrahydroharmol || Serotonin (5-HT)

| Ar-6-OMe || 6-Methoxyharman || 6-Methoxyharmalan || 6-MeO-THH || 5-Methoxytryptamine

| Ar-7-OH || Harmol || Harminol || Tetrahydroharmol || 6-Hydroxytryptamine

| Ar-7-OMe || Harmine || Harmaline || Tetrahydroharmine || 6-Methoxytryptamine

! colspan="5" | with a 1-hydrogen substituent

| Ar-H || βC (norharman) || DHβC || Tryptoline (THβC) || Tryptamine

| Ar-5-OH || 5-HO-βC || 5-HO-DHβC || 5-HO-THβC || 4-Hydroxytryptamine

| Ar-5-OMe || 5-MeO-βC || 5-MeO-DHβC || 5-MeO-THβC || 4-Methoxytryptamine

| Ar-6-OH || 6-HO-βC || 6-HO-DHβC || 6-HO-THβC || Serotonin (5-HT)

| Ar-6-OMe || 6-MeO-βC || 6-MeO-DHβC || Pinoline (6-MeO-THβC) || 5-Methoxytryptamine

| Ar-7-OH || 7-HO-βC || 7-HO-DHβC || 7-HO-THβC || 6-Hydroxytryptamine

| Ar-7-OMe || 7-MeO-βC || 7-MeO-DHβC || 7-MeO-THβC || 6-Methoxytryptamine

|- class="sortbottom"

| colspan="5" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | Refs: || 2,4,5-OMePh || H || Cl || H || H || H || class=skin-invert-image|150px || 5-Chlorotryptamine

Natural occurrence

thumb|300px|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% and 5.9% 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, Lissoclinum fragile or Pseudodistoma aureum.
Nostocarboline was isolated from a freshwater cyanobacterium.
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. Smoking is another source of fully aromatic β-carbolines, with levels up to thousands of μg per smoker each day.
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).

Notes

References

External links

Harmine - TiHKAL - Erowid
Harmaline - TiHKAL - Erowid
Tetrahydroharmine - TiHKAL - Erowid
6-MeO-THH (and Other β-Carbolines) - TiHKAL - Erowid