2. Academic Validation
  3. 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 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 Aug 9;15(8):248. doi: 10.3390/md15080248.
Mohamed A Ibrahim 1 2 3,  Abir T El-Alfy 4 5,  Kelly Ezel 6,  Mohamed O Radwan 7 8,  Abbas G Shilabin 9 10,  Anna J Kochanowska-Karamyan 11 12,  Howaida I Abd-Alla 13,  Masami Otsuka 14,  Mark T Hamann 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA. mmibrahi@olemiss.edu.
  • 2 National Center for Natural Products Research, the University of Mississippi, University, MS 38677, USA. mmibrahi@olemiss.edu.
  • 3 Department of Chemistry of Natural Compounds, National Research Center, Dokki 12622, Cairo, Egypt. mmibrahi@olemiss.edu.
  • 4 Biopharmaceutical Sciences Department, Medical College of Wisconsin Pharmacy School, Milwaukee, WI 53226, USA. aelalfy@mcw.edu.
  • 5 Department of Pharmacology, The University of Mississippi, University, MS 38677, USA. aelalfy@mcw.edu.
  • 6 Department of Pharmacology, The University of Mississippi, University, MS 38677, USA. dionysus21@yahoo.com.
  • 7 Department of Chemistry of Natural Compounds, National Research Center, Dokki 12622, Cairo, Egypt. mohamedosman251@gmail.com.
  • 8 Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan. mohamedosman251@gmail.com.
  • 9 Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA. SHILABIN@mail.etsu.edu.
  • 10 Department of Chemistry, East Tennessee State University, Johnson City, TN 37614, USA. SHILABIN@mail.etsu.edu.
  • 11 Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA. anna.karamyan@ttuhsc.edu.
  • 12 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, TX 79106, USA. anna.karamyan@ttuhsc.edu.
  • 13 Department of Chemistry of Natural Compounds, National Research Center, Dokki 12622, Cairo, Egypt. howaida_nrc@yahoo.com.
  • 14 Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan. motsuka@gpo.kumamoto-u.ac.jp.
  • 15 Department of Pharmacognosy, The University of Mississippi, University, MS 38677, USA. hamannm@musc.edu.
  • 16 National Center for Natural Products Research, the University of Mississippi, University, MS 38677, USA. hamannm@musc.edu.
  • 17 Department of Pharmacology, The University of Mississippi, University, MS 38677, USA. hamannm@musc.edu.
  • 18 Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA. hamannm@musc.edu.
PMID: 28792478 DOI: 10.3390/md15080248
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.

Keywords

5-Halo N,N-dimethyltryptamine; psychiatric disorders; serotonin receptors.

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