Pharmacological evaluation of new constituents of “Spice”: synthetic cannabinoids based on indole, indazole, benzimidazole and carbazole scaffolds, Clara T. Schoeder et al., 2018

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

Clara T. Schoeder, Cornelius Hess, Burkhard Madea, Jens Meiler, Christa E. Müller

Forensic Toxicology, 2018, 36, 385-403.

Doi : 10.1007/s11419-018-0415-z



Purpose : In 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.

Methods : The 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.

Results : Structure-activity relationships were analyzed. The most potent CB1 receptor agonist of the present series MDMBFUBINACA (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.

Conclusions : These results will be useful to assess the compounds’ toxicological risks and to guide legislation. Further studies on 41 are warranted.

Keywords : Pharmacological evaluation of new synthetic cannabinoids · Affinities for CB1 and CB2
receptors · β-Arrestin assay at GPR18 and GPR55 · cAMP accumulation assay · Benzimidazole and carbazole · Structure-activity relationships



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]. Among these, synthetic cannabinoids feature prominently [2, 3]. Between 2008, when so-called “Spice” products [4] containing synthetic cannabinoids began to appear on the drug market, and 2016, 169 new synthetic cannabinoids were confiscated and identified [2]. 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 Gi proteins including a reduction in intracellular cAMP levels. The main psychoactive effects of cannabinoids are mediated by the CB1 receptor, which is predominantly expressed in the central nervous system [7], while CB2 receptor expression in the brain is restricted to microglial cells [8, 9]. CB2 receptors are highly expressed in the immune system, for example in tonsils and spleen [10, 11]. Activation of the CB2 receptor is considered as a new therapeutic option for the treatment of inflammatory diseases and pain [12, 13].

The plant-derived partial CB1 and CB2 receptor agonist Δ9-tetrahydrocannabinol (Δ9-THC, 1, Fig. 1) is used in therapy to target muscle spasms, nausea and cachexia [14]. The synthetic compound CP55,940 (2, Fig. 1) represents a potent full agonist at both receptor subtypes. A CB1 receptor antagonist, rimonabant, had been approved for the treatment of obesity but was later withdrawn from the market due to side effects resulting in depression and an increased suicide rate [15].