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

Abstract

-1-yl-(1-pentyl-1H-indol-3-yl)methanone] represents the first of several Nalkyl-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.

The chemistry and pharmacology of synthetic cannabinoid SDB‐006 and its regioisomeric fluorinated and methoxylated analogs

“…21,22 Analogs of JWH-018 containing a fluorine substituent (JWH-412, 3) or a methoxy group (JWH-081, 4) on the naphthalene ring have been identified in SC products from the marketplace or authentic SC user specimens. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere.…”

“…[23][24][25][26][27][28] These modifications are not restricted to 3-naphthoylindoles, and several regioisomers and homologues of methoxybenzoylindole SC RCS-4 (5) have also been reported 29,30 despite no precedent in the scientific literature, with position of methoxy substituent affecting cannabinoid potency in vitro. 31,32 The benzylic indole-3-carboxamide SDB-006 (6) was seized in Finland in December 2013, 33 and has since been reported elsewhere. 34,35 Although this compound was unprecedented in the scientific literature at the time of its discovery, other benzylic indole-3-carboxamides had been reported as potent, water-soluble CB 1 receptor agonists.…”

“…In order to elucidate structure-activity relationships (SARs) surrounding SDB-006, and proactively anticipate emergent SCs from this class, the 2-, 3-, and 4-methoxybenzyl, and 2-, 3-, and 4-fluorobenzyl regioisomeric analogs of SDB-006 (7-12 respectively) were synthesized, and their fragmentation patterns in both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF/MS) were characterized. Additionally, the activities of 7-12 at cannabinoid receptors were evaluated in vitro, and compared to values obtained for SDB-006, the structurally related methoxybenzoyl SC RCS-4, 31 and the more recent indazole-carboxamide SC AB-CHMINACA (13), [41][42][43] in the same assay. To assess the in vivo potency of SDB-006 relative to older and more recent SCs, the cannabimimetic activities of SDB-006, RCS-4, and AB-CHMINACA were evaluated in rats using biotelemetry.…”

Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135

“…), 83.8 (d, 1 J C-F = 164.9 Hz, CH 2 ), 47.2 (CH 2 ), 30.1 (d, 2 J C-F = 20.0 Hz, CH 2 ), 29.7 (CH 2 ), 23.0 (d, 3 J C-F = 5.0 Hz, CH 2 ); 19 F NMR (376 MHz, CDCl 3 ): δ -218.6; LRMS (+ESI): m/z 263.9 (100%), 249.9 ([M+H] + , 18 %).In vitro pharmacological assessment of SCs. Mouse AtT-20 neuroblastoma cells stably transfected with human CB 1 or human CB 2 have been previously described14,36,41 and were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), 100 U penicillin/streptomycin, and 300 µg/mL G418. Cells were passaged at 80% confluency as required.…”

“…Structures of selective CB 1 receptor antagonist rimonabant (SR141176, 40) and selective CB 2 receptor antagonist SR144528(41).…”