Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model

Rong, Kuanrong; Li, Ziyun; Wu, Xiaoming; Gao, Shan; Zhao, Jie; Yang, Jing; Jiang, Xiaorui; Zhang, Jing; Tang, Wenjian

doi:10.1016/j.ejmech.2024.117003

European Journal of Medicinal Chemistry

2025

DOI: 10.1016/j.ejmech.2024.117003

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Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model

Kuanrong Rong,

Ziyun Li,

Xiaoming Wu

et al.

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References 63 publications

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

Wang,

Yang,

Rong

et al. 2024

IJMS

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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.

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

Wang,

Yang,

Rong

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

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Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model

Cited by 1 publication

References 63 publications

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

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

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