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Neurochemical binding profiles of novel indole and benzofuran MDMA analogues

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Abstract

3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.

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Acknowledgments

The authors gratefully thank Mr. Yossi Hofi for his excellent technical assistance.

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Authors and Affiliations

  1. Department of Toxicology, Kimron Veterinary Institute, Bet Dagan, Israel

    Jakob A. Shimshoni

  2. Pharmaseed Ltd, Ness Ziona, Israel

    Ilan Winkler

  3. BSC BV Company, Veemarkt 61, Amsterdam, Netherlands

    Ezekiel Golan

  4. Neuropsychopharmacology Unit, Imperial College London, London, UK

    David Nutt

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  1. Jakob A. Shimshoni
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  2. Ilan Winkler
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  3. Ezekiel Golan
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Correspondence to Jakob A. Shimshoni.

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Shimshoni, J.A., Winkler, I., Golan, E. et al. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues. Naunyn-Schmiedeberg's Arch Pharmacol 390, 15–24 (2017). https://doi.org/10.1007/s00210-016-1297-4

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