Beta-Carboline

β-Carboline (9H-pyrido[3,4-b]indole) represents the basic chemical structure for 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. 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. 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. 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. 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.