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Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg.

ABSTRACT: Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3'-angeloyl-4'-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC₅₀?=?9.28 µM), followed by 3'-isovaleryl-4'-(2-methylbutyroyl)khellactone (PJ15) (IC₅₀?=?10.0 ?M). Compound senecioyl-4'-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC₅₀?=?7.22 ?M) and had the highest selectivity index (>?5.54), followed by 3'-senecioyl-4'-(2-methylbutyryl)khellactone (PJ10) and 3',4'-disenecioylkhellactone (PJ4) (IC₅₀?=?10.2 and 10.7 ?M, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with K_i values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (-?9.3 kcal/mol) with AChE than PJ15 (-?7.8 kcal/mol) or PJ5 (- 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (-?10.0 kcal/mol) with BChE was higher than for PJ13 (-?7.7 kcal/mol) or PJ15 (-?8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD.

SUBMITTER: Heo JH

PROVIDER: S-EPMC7730441 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg.

Heo Jeong Hyun JH Eom Bo Hyun BH Ryu Hyung Won HW Kang Myung-Gyun MG Park Jong Eun JE Kim Doo-Young DY Kim Jung-Hee JH Park Daeui D Oh Sei-Ryang SR Kim Hoon H

Scientific reports 20201210 1

Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3'-angeloyl-4'-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC<sub>50</sub> = 9.28 µM), followed by 3'-isovaleryl-4'-(2-methylbutyroyl)khellactone ...[more]

PMID: 33303801

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Project description:IntroductionAcetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two cholinergic enzymes catalyzing the reaction of cleaving acetylcholine into acetate and choline at the neuromuscular junction. Abnormal hyperactivity of AChE and BChE can lead to cholinergic deficiency, which is associated with several neurological disorders including cognitive decline and memory impairments. Preclinical studies support that some cannabinoids including cannabidiol (CBD) and tetrahydrocannabinol (THC) may exert pharmacological effects on the cholinergic system, but it remains unclear whether cannabinoids can inhibit AChE and BChE activities. Herein, we aimed to evaluate the inhibitory effects of a panel of cannabinoids including CBD, Δ8-THC, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabicitran (CBT), cannabidivarin (CBDV), cannabichromene (CBC), and cannabinol (CBN) on AChE and BChE activities.MethodsThe inhibitory effects of cannabinoids on the activities of AChE and BChE enzymes were evaluated with the Ellman method using acetyl- and butyryl-thiocholines as substrates. The inhibition mechanism of cannabinoids on AChE and BChE was studied with enzyme kinetic assays including the Lineweaver-Burk and Michaelis-Menten analyses. In addition, computational-based molecular docking experiments were performed to explore the interactions between the cannabinoids and the enzyme proteins.ResultsCannabinoids including CBD, Δ8-THC, CBG, CBGA, CBT, CBDV, CBC, and CBN (at 200 µM) inhibited the activities of AChE and BChE by 70.8, 83.7, 92.9, 76.7, 66.0, 79.3, 13.7, and 30.5%, and by 86.8, 80.8, 93.2, 87.1, 77.0, 78.5, 27.9, and 22.0%, respectively. The inhibitory effects of these cannabinoids (with IC50 values ranging from 85.2 to >200 µM for AChE and 107.1 to >200 µM for BChE) were less potent as compared to the positive control galantamine (IC50 1.21 and 6.86 µM for AChE and BChE, respectively). In addition, CBD, as a representative cannabinoid, displayed a competitive type of inhibition on both AChE and BChE. Data from the molecular docking studies suggested that cannabinoids interacted with several amino acid residues on the enzyme proteins, which supported their overall inhibitory effects on AChE and BChE.ConclusionCannabinoids showed moderate inhibitory effects on the activities of AChE and BChE enzymes, which may contribute to their modulatory effects on the cholinergic system. Further studies using cell-based and in vivo models are warranted to evaluate whether cannabinoids' neuroprotective effects are associated with their anti-cholinesterase activities.

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Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg.

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Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg.

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