Pharmacological evaluation of new constituents of “Spice”: synthetic cannabinoids based on indole, indazole, benzimidazole and carbazole scaffolds

Abstract

PurposeIn the present study we characterized a series of synthetic cannabinoids containing various heterocyclic scaffolds that had been identified as constituents of “Spice”, a preparation sold on the illicit drug market. All compounds were further investigated as potential ligands of the orphan receptors GPR18 and GPR55 that interact with some cannabinoids.MethodsThe compounds were studied in radioligand binding assays to determine their affinity for human cannabinoid CB1 and CB2 receptors expressed in CHO cells, and in cAMP accumulation assays to study their functionality.ResultsStructure-activity relationships were analyzed. The most potent CB1 receptor agonist of the present series MDMB-FUBINACA (12) (Ki = 98.5 pM) was docked into the human CB1 receptor structure, and a plausible binding mode was identified showing high similarity with that of the co-crystallized THC derivatives. MDMB-CHMCZCA (41) displayed a unique profile acting as a full agonist at the CB1 receptor subtype, but blocking the CB2 receptor completely. Only a few weakly potent antagonists of GPR18 and GPR55 were identified, and thus all compounds showed high CB receptor selectivity, mostly interacting with both subtypes, CB1 and CB2.ConclusionsThese results will be useful to assess the compounds’ toxicological risks and to guide legislation. Further studies on 41 are warranted.Electronic supplementary materialThe online version of this article (10.1007/s11419-018-0415-z) contains supplementary material, which is available to authorized users.

Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market

“…As might be expected from available pharmacological data for structurally similar compounds, 4F‐MDMB‐BINACA has been shown by Jawalosky (as referenced in a recent World Health Organization Critical Review) to bind to the CB 1 receptor (4F‐MDMB‐BINACA at CB 1 : Ki = 14.3 nM; (R)‐(+)‐WIN‐55,212–2: Ki = 172 nM; Δ 9 ‐THC: Ki =22.5 nM using HEK cells and [3H]CP‐55,940 (~1.3 nM) as a radioligand) and to have functional activity as assessed using an adenylate cyclase assay using a cyclic AMP ELISA kit (4F‐MDMB‐BINACA, EC 50 = 0.20 nM (E max = 67.7%); (−)CP‐55,940, EC 50 = 0.40 nM (E max = 95.6%); Δ 9 ‐THC, EC 50 = 14.2 nM (E max = 82.9%)). To the best of the author's knowledge there is currently no publicly available data on the pharmacology of MDMB‐4en‐PINACA; however, based on existing structural–activity relationships it is highly likely to be a potent CB 1 and CB 2 receptor agonist …”

“…This, as well as the enactment of other national and international legislative controls, has led to a proliferation of new SCRA compounds, with 260 SCRAs being reported to the United Nations Office for Drugs and Crime (UNODC) by December 2018 and over 180 reported to the EU Early Warning System. The rate of the emergence of new compounds may be slowing, but there has been a general trend of increasing potency as the understanding of SCRA structure–activity relationships has improved …”

Postmortem distribution of mepirapim and acetyl fentanyl in biological fluid and solid tissue specimens measured by the standard addition method

“…Among these tissue samples, the highest levels of unchanged mepirapim were found in the liver (6300 ng/g) and kidney (5410 ng/g), where drugs are usually metabolized and excreted into urine. It is unknown whether the vendors recommended the users to take high doses of mepirapim to gain sufficient drug effects; actually the affinities of mepirapim for both CB 1 and CB 2 receptors were low [6]. The most important problem for mepirapim is the toxicity of the compound; toxicity, pharmacokinetics and metabolism of this compound are all unknown and remain to be explored.…”

In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB‐CHMINACA via human liver microsome incubation and high‐resolution mass spectrometry

“…MDMB‐CHMINACA was originally presented in a patent produced by Pfizer in 2009 (Example 129 in patent) to study the effects of compounds exhibiting CB 1 binding activity . Multiple studies to determine the CB 1 binding affinity (K i ) and receptor activation were previously conducted by researchers . Binding affinity was assessed through competitive binding assays with [ 3 H]CP 55,940, a cyclohexylphenol class synthetic cannabinoid; receptor activation was tested via a fluorometric imaging plate reader (FLIPR) assay .…”

“…The concentration of MDMB‐CHMINACA at which the activation response was 50% of the response of the normalization compound (EC 50 ), was determined through this assay . A K i value of 0.0944 nM (at CB 1 ) was reported by Buchler et al Schoeder et al reported K i values of 0.135 nM (at CB 1 ), and 0.222 nM (at CB 2 ), demonstrating high affinity for both receptors. THC was also evaluated in the Schoeder et al study, and MDMB‐CHMINACA bound to CB 1 with approximately 30 times greater affinity (THC K i : 3.87 nM at CB 1 ).…”