Agarotetrol

Agarotetrol is the chromone derivative from Agarwood, showing very low phosphodiesterase (PDE) 3A inhibitory activity with IC₅₀ value > 100μM^[1]. The aqueous extract of agarwood is characterized by a high concentration of Agarotetrol, a bioactive compound demonstrating significant sedative properties. Upon thermal activation, Agarotetrol compound releases benzylacetone, a characteristic aromatic constituent^[2]. Agarotetrol serves as a crucial quality control marker for the standardization of agarwood in herbal medicinal preparations^[3].

In vitro, Agarotetrol has potential cell protective activity^[4]. After 24 hours of incubation with 20μM Agarotetrol, the 150μM corticosterone-induced damage in PC12 cells was significantly alleviated, with a cell viability of 79.50 ± 1.79% ^[4]. In silico molecular docking and molecular dynamic simulation showed that Agarotetrol had good binding with humanlegumain protein^[5].

In vivo, Agarotetrol can cross the blood-brain barrier in vivo with an estimated blood-brain barrier penetration value of 0.8 in SD rats^[5]. The combined administration of agarwood essential oil (24.85mg/kg) and agarotetrol-enriched extract powder (7.28mg/kg) (prepared into a cyclodextrin mixture) demonstrated significant pharmacological effects on sleep parameters in p-Chlorophenylalanine-induced insomnia SD rats. Nasal cavity of administration for 7 days resulted in enhanced sleep onset efficiency, reduced sleep latency, and extended total sleep duration ^[6]. Following a 30-day oral administration regimen of Agarotetrol at a dosage of 6.0g/kg/day, comprehensive biodistribution analysis demonstrated a tissue-specific accumulation pattern in experimental rats, with the highest concentration detected in renal tissue, followed by hepatic, cardiac, and cerebral tissues in decreasing order of magnitude^[7].

References:
[1] Sugiyama T, Narukawa Y, Shibata S, et al. Three new 5, 6, 7, 8-tetrahydroxy-5, 6, 7, 8-tetrahydrochromone derivatives enantiomeric to agarotetrol from agarwood[J]. Journal of natural medicines, 2018, 72: 667-674.
[2] Takamatsu S, Ito M. Agarotetrol: a source compound for low molecular weight aromatic compounds from agarwood heating[J]. Journal of natural medicines, 2018, 72: 537-541.
[3] Takamatsu S, Ito M. Agarotetrol as an index for evaluating agarwood in crude drug products[J]. Journal of Natural Medicines, 2022, 76(4): 857-864.
[4] Zhang L, Yi P, Yan H, et al. Five new 2-(2-phenylethyl) chromone derivatives and three new sesquiterpenoids from the heartwood of Aquilaria sinensis, an aromatic medicine in China[J]. Natural Products and Bioprospecting, 2022, 12(1): 2.
[5] Alugoju P, Bhandare V V, Patil V S, et al. In silico molecular docking and molecular dynamic simulation of agarwood compounds with molecular targets of Alzheimer’s disease[J]. F1000Research, 2024, 12: 230.
[6] Lai Y, Hua L, Yang J, et al. The effect of Chinese agarwood essential oil with cyclodextrin inclusion against PCPA-induced insomnia rats[J]. Molecules, 2023, 28(2): 635.
[7] Hou H, Chen T, Xu Z, et al. Study and exploration of the pharmacokinetics of traditional Tibetan medicine Ruyi Zhenbao tablets after single and long-term administration[J]. Frontiers in Pharmacology, 2022, 13: 948693.

Agarotetrol是从沉香中分离得到的一种色酮衍生物，对磷酸二酯酶3A（PDE 3A）的抑制活性较弱，IC₅₀值大于100μM^[1]。沉香水提物的特征性成分是含有高浓度的Agarotetrol，Agarotetrol具有显著的镇静作用。在热活化条件下，Agarotetrol可释放出特征性芳香成分苯乙酮。Agarotetro已成为沉香药材质量控制的重要标志物，在中药制剂标准化过程中发挥关键作用^[3]。

在体外，Agarotetrol具有潜在的细胞保护活性^[4]。当PC12细胞与20μM Agarotetrol共孵育24小时后，150μM皮质酮诱导的细胞损伤得到显著缓解，细胞存活率达到79.50 ± 1.79%^[4]。通过分子对接和分子动力学模拟分析，Agarotetrol与humanlegumain蛋白具有良好的结合特性^[5]。

Agarotetrol在体内能够穿透血脑屏障，在SD大鼠血脑屏障透过率估计值为0.8 ^[5]。将沉香精油（24.85mg/kg）与富含Agarotetrol的提取物粉末（7.28mg/kg）制备成环糊精混合物后联合给药，在对氯苯丙氨酸诱导的失眠SD大鼠模型中显示出显著的睡眠参数改善作用。经鼻腔给药7天后，可提高睡眠起始效率、缩短睡眠潜伏期并延长总睡眠时间^[6]。在SD大鼠中进行为期30天、剂量为6.0 g/kg/天的Agarotetrol口服给药后，Agarotetrol具有组织特异性分布模式，其中肾脏组织中的浓度最高，其次是肝脏、心脏和脑组织，呈递减趋势^[7]。