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. 2024 Nov 5;25(22):11888.
doi: 10.3390/ijms252211888.

Structure-Tissue Exposure/Selectivity Relationship (STR) on Carbamates of Cannabidiol

Sheng Wang  1 , Jian-Guo Yang  1 , Kuanrong Rong  1 , Huan-Huan Li  1 , Chengyao Wu  1 , Wenjian Tang  1
Affiliations

Structure-Tissue Exposure/Selectivity Relationship (STR) on Carbamates of Cannabidiol

Sheng Wang et al. Int J Mol Sci. .

Abstract

The structure-tissue exposure/selectivity relationship (STR) aids in lead optimization to improve drug candidate selection and balance clinical dose, efficacy, and toxicity. In this work, butyrocholinesterase (BuChE)-targeted cannabidiol (CBD) carbamates were used to study the STR in correlation with observed efficacy/toxicity. CBD carbamates with similar structures and same molecular target showed similar/different pharmacokinetics. L2 and L4 had almost same plasma exposure, which was not correlated with their exposure in the brain, while tissue exposure/selectivity was correlated with efficacy/safety. Structural modifications of CBD carbamates not only changed drug plasma exposure, but also altered drug tissue exposure/selectivity. The secondary amine of carbamate can be metabolized into CBD, while the tertiary amine is more stable. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters can be used to predict STR. Therefore, STR can alter drug tissue exposure/selectivity in normal tissues, impacting efficacy/toxicity. The drug optimization process should balance the structure-activity relationship (SAR) and STR of drug candidates for improving clinical trials.

Keywords: butyrocholinesterase; cannabidiol; carbamate; drug development and optimization; structure–activity relationship (SAR); structure–tissue exposure/selectivity relationship (STR).

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of CBD and its carbamates L1–L4 used in this study. Compound inhibits the activity of the enzymes acetylcholinesterase (AChE) or BuChE, which catalyzes the degradation/hydrolysis of the neurotransmitter acetylcholine. IC50 values were defined as the concentration of compound where percent inhibition rate on the BuChE inhibition is equal to 50 and was the mean from three independent experiments in this study.
Figure 2
Figure 2
(A) The drug concentration and AUC in plasma and target tissue (brain) after oral administration of L2 and L4 in rats: plasma AUC vs. tissue AUC of brain. (B) Concentration–time curve of L2 vs. L4 in the plasma. (C) Concentration–time curve of L2 vs. L4 in the brain.
Figure 3
Figure 3
Drug tissue selectivity is a critical parameter that tips the balance of efficacy/toxicity. Comparison of drug exposure (A) and selectivity (B) in brain, liver, and kidney tissues between L2 and L4 after oral administration (15 mg/kg), *** p < 0.05, **** p < 0.01.
Figure 4
Figure 4
Structural modification alters drug exposure and selectivity in tissues despite similar exposure in plasma. (A) Concentration–time curve of L2 vs. L4 in tissues. (B) AUC ratio of L2 vs. L4.
Figure 5
Figure 5
Average blood concentration–time curve of each analyte (n = 5).
See this image and copyright information in PMC

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