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Structure–activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues

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Abstract

RCS-4 [(4-methoxyphenyl)-1-yl-(1-pentyl-1H-indol-3-yl)methanone] represents the first of several N-alkyl-3-(methoxybenzoyl)indoles identified by forensic scientists as synthetic cannabinoid (SC) designer drugs. Despite the detection of RCS-4 and several analogues (RCS-2, RCS-3, RCS-2-C4, RCS-3-C4, and RCS-4-C4) in products intended for human consumption, relatively little is known about this class of cannabinoids. The synthesis of all regioisomers of RCS-4 and their C4 homologues is described. This study also systematically explored the structure–activity relationships of this class of SCs at human CB1 and CB2 receptors using an in vitro fluorometric imaging plate reader membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 54–574 nM) and CB2 (EC50 = 4.5–46 nM) receptors, with the C4 homologues showing a preference for CB2 receptors over CB1 receptors (31–42 times). Since most of the analogues (RCS-2, RCS-3, RCS-2-C4, RCS-3-C4 and RCS-4-C4) are not subject to regulation in much of the world, despite their activities towards CB1 and CB2 receptors, there is a possibility that these analogues will emerge on the black market.

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Acknowledgments

Work was supported in part by the European Union’s Seventh Framework Programme [FP7/2007–2013] INMiND (Grant agreement No. HEALTH-F2-2011-278850). MC was supported by NHMRC Project Grant 1002680, and JS by an iMQRES Postgraduate Scholarship from Macquarie University.

Conflict of interest

There are no financial or other relations that could lead to a conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Authors and Affiliations

  1. Department of Radiology, Stanford University School of Medicine, Stanford, USA

    Samuel D. Banister & Corinne Beinat

  2. School of Chemistry, The University of Sydney, Sydney, Australia

    Samuel D. Banister, Trent Conroy, Mitchell Longworth, Madhura Manohar, Corinne Beinat, Shane M. Wilkinson & Michael Kassiou

  3. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

    Jordyn Stuart & Mark Connor

  4. Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Trent Conroy

  5. Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Trent Conroy

  6. School of Psychology, The University of Sydney, Sydney, Australia

    Richard C. Kevin & Iain S. McGregor

  7. Faculty of Pharmacy, The University of Sydney, Sydney, Australia

    David E. Hibbs

  8. School of Medical Sciences, The University of Auckland, Auckland, New Zealand

    Michelle Glass

  9. Faculty of Health Sciences, The University of Sydney, Sydney, Australia

    Michael Kassiou

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  1. Samuel D. Banister
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Correspondence to Michael Kassiou.

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Banister, S.D., Stuart, J., Conroy, T. et al. Structure–activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues. Forensic Toxicol 33, 355–366 (2015). https://doi.org/10.1007/s11419-015-0282-9

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