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Marine Indole Alkaloids as Potential Antidepressant Agents

introduction of fluorine at position 6 of N,N-dimethyltryptamine causes a 5-fold decrease in affinity toward the 5-HT1A receptor…”

According to self-reported data gathered by the Office for National Statistics (ONS), depression is on the increase worldwide, particularly among young people.

The anxiety disorders that often co-occur with other psychiatric illnesses such as depression, affect around 40 million American adults each year. If the increase continues at the current rate, it is estimated that, by 2020, depression will be the most disabling condition after heart disease.

Both anxiety and depression are often treated using antidepressants. Although these medications can help people to manage their symptoms, they do not generally lead to people being free of depression for the rest of their lives.

Furthermore, the drugs are associated with adverse side effects such as sexual dysfunction and weight gain. Sedatives can also be used to treat anxiety, but these can cause headaches, drowsiness and dizziness.

Mark Hamann and team from the University of Mississippi say there is clearly a need for alternative depression and anxiety treatments that are more effective and safer to use. Recently, they carried out a study into marine-derived indole alkaloids as potential modulators of neurological receptors.

Such compounds have previously shown high affinity binding for serotonin receptors. Serotonin is a mood elevating neurotransmitter that current antidepressants increase levels of in the brain by inhibiting its catabolism or reuptake.

Hamman and colleagues prepared various derivatives of the indole alkaloid 2-(1H-indol-3-yl)-N,N-dimethylethanamine with different halogen substitutions. Halogens compounds, which are those containing halogen atoms such as bromine, fluorine or chlorine, are often included in drug design strategies because they improve potency and impact on target selectivity.

The team assessed the in vitro and in vivo antidepressant and sedative activities of the compounds using the forced swim test and locomotor activity test.

They found that, of the compounds they synthesized, six exhibited significant anti-depressant activity, namely 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1a), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1d), 2-(1H-indol-3-yl)-N,N-dimethylethanamine (2a), 2-(5-chloro-1H-indol-3-yl)-N,N-dimethylethanamine (2c), 2-(5-bromo-1H-indol-3-yl)-N,N-dimethylethanamine (2d), and 2-(5-iodo-1H-indol-3-yl)-N,N-dimethylethanamine (2e).

Of these, the latter three compounds (2c, 2d, 2e), also demonstrated significant sedative activity.

The team then tested the compounds receptor binding capability and found that 2a, 2c, 2d and 2e all showed nanomolar affinities to the serotonin receptors 5-HT1A and 5-HT7.

For the study, the researchers used mass spectrometry and nuclear magnetic resonance imaging, which were carried out using Bruker’s high-performance scientific instrumentation. Mass spectra were recorded on Bruker’s micrOTOF and 1D and 2D NMR experiments were performed using Bruker’s DRX NMR spectrometer.

NMR allowed the researchers to show that the antidepressant action exerted by some of the compounds was at least partly mediated through their interaction with serotonin receptors.

The researchers add that further mechanistic studies are needed to delineate these interactions and to clarify the mechanism underlying the behavioural effects the compounds had.

Contact Bruker for more information about the DRX NMR spectrometer.

Reference:

  • Hamann, M et al. Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space. Marine Drugs 2017, 15(8), 248; doi:3390/md15080248