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Mar. Drugs 2017, 15(8), 248; doi:10.3390/md15080248

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

1
Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA
2
National Center for Natural Products Research, the University of Mississippi, University, MS 38677, USA
3
Department of Chemistry of Natural Compounds, National Research Center, Dokki 12622, Cairo, Egypt
4
Biopharmaceutical Sciences Department, Medical College of Wisconsin Pharmacy School, Milwaukee, WI 53226, USA
5
Department of Pharmacology, The University of Mississippi, University, MS 38677, USA
6
Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan
7
Department of Chemistry, East Tennessee State University, Johnson City, TN 37614, USA
8
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, TX 79106, USA
9
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
*
Author to whom correspondence should be addressed.
Received: 21 June 2017 / Revised: 28 July 2017 / Accepted: 31 July 2017 / Published: 9 August 2017
(This article belongs to the Special Issue Synthesis of Marine-Derived Compounds)
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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. View Full-Text
Keywords: serotonin receptors; psychiatric disorders; 5-Halo N,N-dimethyltryptamine serotonin receptors; psychiatric disorders; 5-Halo N,N-dimethyltryptamine
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MDPI and ACS Style

Ibrahim, M.A.; El-Alfy, A.T.; Ezel, K.; Radwan, M.O.; Shilabin, A.G.; Kochanowska-Karamyan, A.J.; Abd-Alla, H.I.; Otsuka, M.; Hamann, M.T. 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. Mar. Drugs 2017, 15, 248.

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