Citation

Schoeder CT, Hess C, Madea B, Meiler J, Müller CE. Forensic Toxicol. 2018; 36(2): 385-403.

Affiliation

3Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.

Copyright

(Copyright © 2018, Holtzbrinck Springer Nature Publishing Group)

DOI

10.1007/s11419-018-0415-z

PMID

29963207

PMCID

PMC6002460

Abstract

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 MDMB-FUBINACA (12) (K_i = 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.

Language: en

Keywords

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