Abstract
In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo-N,N-dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1H-indol-3-yl)-N,N-dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 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) have been shown to possess significant antidepressant-like action, while compounds 2c, 2d, and 2e exhibited potent sedative activity. Compounds 2a, 2c, 2d, and 2e showed nanomolar affinities to serotonin receptors 5-HT1A and 5-HT7. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.
Highlights
Depression is the most common neuropsychiatric disorder affecting approximately 7% of Americans each year [1]
According to the National Institute of Mental Health (NIMH), every year about 40 million American adults suffer from anxiety disorders that frequently co-occur with other psychiatric illnesses, like depression [2]
Various marine natural products have been reported as valuable drug leads for neurological disorders and here we illustrate the unique activity of brominated molecules supporting the value of brominated marine natural products in the selectivity for neurological receptors and other target proteins [3,4,5]
Summary
Depression is the most common neuropsychiatric disorder affecting approximately 7% of Americans each year [1]. Halogens are included in rational drug design strategies primarily to enhance membrane permeability [13], fill spaces in the binding pocket, and decrease metabolic degradation They can improve potency and impact target selectivity by affecting pKa and by changing conformation, lipophilicity, and hydrophobic interactions especially in hydrophobic pockets such those of serotonin receptors 5-HT1A and 5-HT7. We considered fluorine incorporation into our derivatives due to its emerging application in positron emission tomography (PET) which enhances its utility for central nervous system (CNS) drug discovery. This is attributed to the favorable 18 F half-life (109.8 min) when compared to 13 C (20.4 min) and 124 I (4.2 days) [18,19,20]. We considered the incorporation of different halogen atoms in our design
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