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.
Highlights
A challenging issue for forensic toxicologists and law makers is how to effectively respond to the constantly changing new psychoactive substances on the illicit drug market [1]
CB receptors are divided into two subtypes, CB1 and CB2, which belong to the large family of rhodopsin-like class A G protein-coupled receptors (GPCRs) [6]
In the present study, CB1 and CB2 receptor affinities of a new series of synthetic cannabinoids were determined in radioligand binding studies, which provide an ideal basis for the analysis of structure-activity relationships (SARs) (Table 1)
Summary
A challenging issue for forensic toxicologists and law makers is how to effectively respond to the constantly changing new psychoactive substances on the illicit drug market [1]. Most of them were discovered as powders, often in bulk amounts, while others were found in preparations of plant materials, e.g., minced herbs, onto which solutions of the cannabinoids had been sprayed [5]. These substances have been shown to bind to and in many cases activate cannabinoid (CB) receptors. CB receptors are divided into two subtypes, CB1 and CB2, which belong to the large family of rhodopsin-like class A G protein-coupled receptors (GPCRs) [6] Both CB receptor subtypes are coupled to G i proteins including a reduction in
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