Pharmacological characterization of emerging hexahydrocannabinol-derived semi-synthetic cannabinoids at the cannabinoid type 1 receptor using a β-arrestin2 recruitment assay.
Abstract
Semi-synthetic cannabinoids (SSCs) represent a rapidly expanding subclass of cannabinoids on the recreational drug market. Among these, structurally modified hexahydrocannabinol (HHC) derivatives have become particularly prominent. Fourteen HHC-derived SSCs were investigated, comprising C3 butyl to nonyl (C4-C9) side chain variants and C1-esterified derivatives of HHC and hexahydrocannabiphorol (HHCP). For each compound, the individual 9(R)- and 9(S)-epimers were evaluated. As a proxy for abuse potential, the compounds (picomolar-micromolar concentrations) were evaluated for cannabinoid type 1 receptor (CB1) activation potential using a cell-based β-arrestin2 recruitment bioassay, enabling determination of potency (EC50) and efficacy (Emax) values. Structure-activity relationship (SAR) analysis demonstrated that elongation of the C3 alkyl side chain increased efficacy (C4 C9). The heptyl derivatives represented an exception to this trend, showing comparable or reduced efficacy relative to their hexyl counterparts, while maintaining similar or slightly increased potency. Notably, the C8 and C9 derivatives displayed markedly high efficacies, approaching or even exceeding the efficacy of the synthetic cannabinoid receptor agonist reference CP55,940. C1 esterification markedly reduced potency, with a less pronounced effect on efficacy. Across all compounds, the 9(R)-epimers were consistently more potent than their 9(S)-counterparts, while effects on efficacy were more variable and dependent on the specific structural modification. Overall, these findings enabled differentiation between compounds with negligible, comparable or higher activity at CB1 than ∆9-THC. This information may support healthcare workers and allow prioritization of substances that warrant extra surveillance.
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