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

• Published in: Marine drugs 2017-08, Vol.15 (8), p.248
• Main Authors: Ibrahim, Mohamed A, El-Alfy, Abir T, Ezel, Kelly, Radwan, Mohamed O, Shilabin, Abbas G, Kochanowska-Karamyan, Anna J, Abd-Alla, Howaida I, Otsuka, Masami, Hamann, Mark T
• Format: Article
• Language: English
• Subjects: 5-Halo N,N-dimethyltryptamine; Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Alkaloids; Animals; Antidepressants; Antidepressive Agents - chemistry; Bromine; Drug development; Drugs; Electrostatic properties; Halogens; Hydrocarbons, Brominated - chemistry; In vitro methods and tests; In vivo methods and tests; Indole Alkaloids - pharmacology; Indoles; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Interactions; Locomotor activity; Marine Biology; Marine chemistry; Marine environment; Metabolites; Mice; Modulators; N,N-Dimethyltryptamine - analogs & derivatives; N,N-Dimethyltryptamine - chemistry; N,N-Dimethyltryptamine - pharmacology; Natural products; psychiatric disorders; Receptors; Receptors, Serotonin - drug effects; Serotonin; Serotonin receptors; Serotonin S1 receptors; Serotonin S7 receptors; Synthesis
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md15080248

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- , -dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1 -indol-3-yl)- , -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-(1 -indol-3-yl)- , -dimethyl-2-oxoacetamide ( ), 2-(5-bromo-1 -indol-3-yl)- , -dimethyl-2-oxoacetamide ( ), 2-(1 -indol-3-yl)- , -dimethylethanamine ( ), 2-(5-chloro-1 -indol-3-yl)- , -dimethylethanamine ( ), 2-(5-bromo-1 -indol-3-yl)- , -dimethylethanamine ( ), and 2-(5-iodo-1 -indol-3-yl)- , -dimethylethanamine ( ) have been shown to possess significant antidepressant-like action, while compounds , , and exhibited potent sedative activity. Compounds , , , and showed nanomolar affinities to serotonin receptors 5-HT 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.