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
Mohamed A. Ibrahim, Abir T. El-Alfy, Kelly Ezel, Mohamed O. Radwan, Abbas G. Shilabin, Anna J. Kochanowska-Karamyan, Howaida I. Abd-Alla, Masami Otsuka, Mark T. Hamann
Marine Drugs October 26, 2018 DOI: 10.3390/md15080248 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | 2-(1H-indol-3-yl)-N N-dimethyl-2-oxoacetamide (1a) 2-(5-bromo-1H-indol-3-yl)-N N-dimethyl-2-oxoacetamide (1d) N-dimethylethanamine (2a) 2-(5-chloro-1H-indol-3-yl)-N N-dimethylethanamine (2c) N-dimethylethanamine (2d) 2-(5-iodo-1H-indol-3-yl)-N N-dimethylethanamine (2e) |
| Topics | Serotonin |
| Keywords | Serotonin receptors Psychiatric disorders 5-Halo N,N-Dimethyltryptamine |
| Citations | 22 |
| Key findings | Six halogen-substituted tryptamine compounds showed significant antidepressant-like action in mice, with three also exhibiting potent sedative activity, and four compounds bound to serotonin receptors 5-HT1A and 5-HT7 with nanomolar affinities. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 5
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- Human psychopharmacology of N,N-dimethyltryptamine Behavioural Brain Research December 1, 1995
- Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Pharmacology, Biochemistry, and Behavior November 1, 1998
- Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans Biological Psychiatry May 1, 1996
- Secondary metabolites from three Florida sponges with antidepressant activity. Journal of Natural Products January 25, 2008