Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14–17) showed affinities for CB1 (K i = 47.9–813 nM) and CB2 (K i = 47.9–347 nM) that were intermediate to that of the corresponding benzylic (10–13, CB1 K i = 550 nM to >10 μM; CB2 K i = 61.7 nM to >10 μM) and cumyl derivatives (6–9, CB1 K i = 12.6–21.4 nM; CB2 K i = 2.95–24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32–464 nM; E max = 89–104%) and low efficacy agonists of CB2 (EC50 = 54–500 nM; E max = 52–77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14–17 compared to (R)-14–17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.

Overview of Synthetic Cannabinoids ADB-FUBINACA and AMB-FUBINACA: Clinical, Analytical, and Forensic Implications

“…Antonides et al [31] analysed sized herbal products, reporting a predominance of the (S)-enantiomer of AMB-FUBINACA in all samples (96.8 to 98.2%), which is in line with studies revealing the (S)-enantiomer of other SCs as the most prevalent or the only detected in illicit herbal products [30]]. Of note, the (S)-enantiomer is generally more potent than the (R)-enantiomer in both CB1R and CB2R [30,32,34], the potency varying amongst SCs [31,33]. In this line, (S)-AMB-FUBINACA has greater ADB-FUBINACA is the methylated analogue of the SC AB-FUBINACA (Figure 1), which was also developed and patented (patent reference: WO 2009/106980-A2) by Ingrid Buchler and her colleagues at Pfizer Inc. in 2009, having never been tested in humans [8,29].…”

“…The potency in the (R)-enantiomer increases for SCs displaying the configuration of valinate methyl ester, at the detriment of valinamide, leucinamide or tert-leucine methyl ester. In addition, the efficacy of the (S)-AMB-FUBINACA was also found to be almost two times greater in CB1R, with a maximal response (E max ) of 267% for the (S)-enantiomer and 154% for the (R)-enantiomer, as compared to the control (JWH-018); while the efficacy in CB2R was lower for the (S)-enantiomer (E max of 161%), when compared to the (R)-enantiomer (E max of 205%) [31,33,34].…”

“…AMB-FUBINACA has also the (S)-and (R)-configurations and the chiral centre at the C-2 carbon of the valinate side chain [29]. Chirality is common among SCs, implying different pharmacological and toxicological potencies among enantiomers [30][31][32][33][34]. As such, the assessment of the proportions of (S)-and (R)-enantiomers in the seized materials may allow for a better estimate of the risks users are exposed to.…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Halogenated JWH-018 was less effective in causing seizures, myoclonia, and hyperreflexia than JWH-018 [ 83 ]. Moreover, the enantiomeric configuration might have a role in the affinity to receptors [ 84 , 85 ].…”

“…Harmful effects of NPS have been repeatedly proven to be fatal as reported by case reports, case series, and reviews present in the literature [ 7 , 85 , 165 , 166 , 167 , 168 ]. Also, data from studies applied to animals, conducted so far mostly in mice, unequivocally draw great attention to the acute toxic effects of these chemicals [ 169 , 170 , 171 ].…”