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Log D_7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity

Lookup NU author(s): Dr Andrew BrandonORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D_7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market.

Publication metadata

Author(s): Brandon AM, Baginski SR, Peet C, Dugard P, Gréen H, Sutcliffe OB, Nic Daéid N, Nisbet LA, Read KD, McKenzie C

Publication type: Article

Publication status: Published

Journal: Drug Testing and Analysis

Year: 2024

Volume: 16

Issue: 9

Pages: 1012-1025

Print publication date: 01/09/2024

Online publication date: 08/12/2023

Acceptance date: 15/11/2023

Date deposited: 15/12/2023

ISSN (print): 1942-7603

ISSN (electronic): 1942-7611

Publisher: John Wiley & Sons Ltd

URL: https://doi.org/10.1002/dta.3621

DOI: 10.1002/dta.3621

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