Pharmacological evaluation of synthetic cannabinoids identified as constituents of spice

Abstract

In recent years, many synthetic cannabinoid (CB) receptor agonists have appeared on the market as constituents of herbal incense mixtures known as “spice”. Contrary to the declared use, they are perorally consumed as a replacement for marijuana to get “high”. In many cases, detailed information on the physicochemical and pharmacological properties of the synthetic compounds found in spice preparations is lacking. We have now evaluated a large series of heterocyclic compounds, 1,3-disubstituted indole and 2-azaindole derivatives known or assumed to be CB1 receptor agonists, many of which have previously been identified in forensic samples. The mainly observed structural variations to circumvent restriction by law were bioisosteric exchanges of functional groups in known CB1 agonists. We analyzed the structure-activity relationships of compounds at human CB1 and CB2 receptors based on affinities obtained in radioligand binding studies, and determined their efficacy in cAMP accumulation assays. Moreover, we investigated the activities of the compounds at the orphan G protein-coupled receptors GPR18 and GPR55 both of which are known to interact with cannabinoids. Most of the investigated compounds behaved as potent full agonists of CB1 and CB2 receptors with affinities in the low nanomolar to subnanomolar concentration range. Some compounds were moderately potent GPR55 antagonists, while none interacted with GPR18. Most derivatives were predicted to cross the blood–brain barrier as determined by bioinformatics tools. These data are useful for assessing synthetic cannabinoids and will be helpful for predicting pharmacological properties of novel compounds that appear on the illicit drug market.Electronic supplementary materialThe online version of this article (doi:10.1007/s11419-016-0320-2) contains supplementary material, which is available to authorized users.

Synthetic Pot: Not Your Grandfather’s Marijuana

“…Upon analysis of these herbal mixtures, the synthetic cannabimimetics JWH-018 and CP 47,497-C8 were identified as the primary psychoactive components [1]. Since then, several structural classes of SCBs have quickly evolved and diversified to avoid forensic detection and legislative scheduling [1, 5]. Individual users have sought after SCBs to avoid detection in standardized drug testing as well as to achieve a more intense high than that associated with marijuana [3].…”

“…Aside from the major chemical classes of SCBs, including classical cannabinoids, cyclohexyl-substituted phenols, naphthoylindols, and benzoylindoles, newer SCB structures such as tetramethylcyclopropylindoles, adamantoylindoles, indazole carboximides and quinolinyl esters have been popularized in K2/Spice products [5, 23] (Figure 1). While these SCBs have been advertised as “synthetic marijuana,” when compared to Δ 9 -THC, they are structurally heterologous.…”

Elucidation of the fluorine substitution position on the phenyl ring of synthetic cannabinoids by electron ionization-triple quadrupole mass spectrometry

“…Several research groups have reported diŠerentiations of structural isomers based on diŠerences in the fragment ions in full scan/ product ion scan mass spectra 6 12) . However, a group of SCs containing a ‰uorobenzyl group at the N-1 position, including N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-‰urobenzyl)-1H-indazole-3-carboxamide ( AB-FUBINACA ) 13,14) , N-( 1-amino-3,3-dimethyl-1-oxobutan-2-yl ) -1-( 4-‰urobenzyl ) -1H-indazole-3-carboxamide ( ADB-FUBINACA ) 14,15) , methyl 2-[ 1-( 4-‰uorobenzyl ) -1H-indazole-3-carboxamido ] -3-methylbutanoate ( FUB-AMB; AMB-FUBINACA) 16) , and N-(1-adamantyl)-1-(4-‰uorobenzyl ) -1H-indazole-3-carboxamide ( FUB-APINACA; FUB-AKB48 ) 17) , were di‹cult to distinguish from their ‰uorine positional isomers in both full scan and product ion scan mass spectra because few characteristic fragment ions were observed. Contributing to this challenge was the fact that the reference standards for the positional isomers were not readily available on the market.…”

To prohibit or regulate psychoactive substances: has New Zealand got the right approach?

“…Several drug addiction services have reported an increase in synthetic cannabis users reverting back to methamphetamine. Prosecutions under the Misuse of Drugs Act for possessing, supplying, administering, or dealing in methamphetamine and amphetamine have risen, 26 and methamphetamine seizures increased by more than nine times between 2013 and 2015. 32…”

“…Many of the synthetic cannabinoid legal highs are assumed to be cannabinoid receptor agonists but a large proportion have mixed pharmacology. 26 The New Zealand Act permits approved licence holders to conduct scientific research with potential psychoactive substances, 27 although research organisations have to pay a substantial fee for this licence. At the time of writing there were "eight licences to research" listed on the government website, 28 four of which were to universities or crown owned organisations.…”