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

• Published in: Forensic toxicology Vol. 33; no. 2; pp. 355 - 366
• Main Authors: Banister, Samuel D., Stuart, Jordyn, Conroy, Trent, Longworth, Mitchell, Manohar, Madhura, Beinat, Corinne, Wilkinson, Shane M., Kevin, Richard C., Hibbs, David E., Glass, Michelle, Connor, Mark, McGregor, Iain S., Kassiou, Michael
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.07.2015
• Subjects: Forensic Medicine; Forensic Science; Medical Law; Medicinal Chemistry; Medicine; Medicine & Public Health; Original Article; Pharmacology/Toxicology; Synthetic cannabinoid; RCS-2-C4; RCS-4 analogues; RCS-4-C4; Structure–activity relationship
• ISSN: 1860-8965; 1860-8973
• DOI: 10.1007/s11419-015-0282-9

RCS-4 [(4-methoxyphenyl)-1-yl-(1-pentyl-1 H -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 CB 1 and CB 2 receptors using an in vitro fluorometric imaging plate reader membrane potential assay. All compounds demonstrated agonist activity at CB 1 (EC 50  = 54–574 nM) and CB 2 (EC 50  = 4.5–46 nM) receptors, with the C4 homologues showing a preference for CB 2 receptors over CB 1 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 CB 1 and CB 2 receptors, there is a possibility that these analogues will emerge on the black market.