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New synthetic cannabinoids carrying a cyclobutyl methyl side chain: Human Phase I metabolism and data on human cannabinoid receptor 1 binding and activation of Cumyl‐CBMICA and Cumyl‐CBMINACA
Author(s) -
Haschimi Belal,
Grafinger Katharina Elisabeth,
Pulver Benedikt,
Psychou Evangelia,
Halter Sebastian,
Huppertz Laura M.,
Westphal Folker,
Pütz Michael,
Auwärter Volker
Publication year - 2021
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.3038
Subject(s) - chemistry , cannabinoid receptor , cannabinoid , synthetic cannabinoids , indole test , potency , hydroxylation , cannabinoid receptor agonists , metabolite , microsome , receptor , in vivo , moiety , ligand (biochemistry) , cannabinol , stereochemistry , in vitro , pharmacology , biochemistry , antagonist , biology , microbiology and biotechnology , enzyme
Synthetic cannabinoids (SCs) represent a large group of new psychoactive substances (NPS), sustaining a high prevalence on the drug market since their first detection in 2008. Cumyl‐CBMICA and Cumyl‐CBMINACA, the first representatives of a new subclass of SCs characterized by a cyclobutyl methyl (CBM) moiety, were identified in July 2019 and February 2020. This work aimed at evaluating basic pharmacological characteristics and human Phase I metabolism of these compounds. Human Phase I metabolites were tentatively identified by liquid chromatography–quadrupole time‐of‐flight mass spectrometry (LC‐QToF‐MS) of urine samples and confirmed by a pooled human liver microsome (pHLM) assay. The basic pharmacological evaluation was performed by applying a competitive ligand binding assay and a functional activation assay (GTPγS) using cell membranes carrying the human cannabinoid receptor 1 (hCB 1 ). Investigation of the human Phase I metabolism resulted in the identification of specific urinary markers built by monohydroxylation or dihydroxylation. Although Cumyl‐CBMICA was primarily hydroxylated at the indole ring, hydroxylation of Cumyl‐CBMINACA mainly occurred at the CBM moiety. Both substances acted as agonists at the hCB 1 receptor, although substantial differences could be observed. Cumyl‐CBMINACA showed higher binding affinity ( K i = 1.32 vs. 29.3 nM), potency (EC 50 = 55.4 vs. 497 nM), and efficacy ( E max = 207% vs. 168%) than its indole counterpart Cumyl‐CBMICA. This study confirms that substitution of an indole by an indazole core tends to increase in vitro potency, which is potentially reflected by higher in vivo potency. The emergence and disappearance of SCs distributed via online shops carrying a CBM moiety once more demonstrate the “cat‐and‐mouse” game between manufacturers and legislation.