先进的构效关系在荆芥挥发油化合物作为 AChE 和 NMDA 配体方面的应用，与多奈哌齐、加兰他敏和美金刚的比较-脑疾病药理学的新方法。

Advanced Structure-activity Relationships Applied to Mentha spicata L. Subsp. spicata Essential Oil Compounds as AChE and NMDA Ligands, in Comparison with Donepezil, Galantamine and Memantine - New Approach in Brain Disorders Pharmacology.

机构信息

Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest. Romania.

Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95th Spl. Independentei: 050095, Bucharest. Romania.

出版信息

CNS Neurol Disord Drug Targets. 2017;16(7):800-811. doi: 10.2174/1871527316666170113115004.

DOI:10.2174/1871527316666170113115004

PMID:28088901

Abstract

BACKGROUND

Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy.

OBJECTIVE

We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil.

METHOD

We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine.

RESULTS

The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2).

CONCLUSION

Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders.

摘要

背景

阿尔茨海默病（AD）的治疗基于几种天然和合成化合物，这些化合物作为乙酰胆碱酯酶（AChE）和 N-甲基-D-天冬氨酸受体（NMDA）配体，在缓解 AD 症状方面的效果有限。最近的研究表明，从薄荷（Mentha spicata L. subsp. spicata）分离出的抑制剂有望用于 AD 治疗。

目的

我们旨在通过考虑薄荷（Mentha spicata L. subsp. spicata）精油中的化合物，确定用于 AD 治疗的新型、更有效的植物药化合物。

方法

我们通过将 14 种薄荷（Mentha spicata L. subsp. spicata）化合物的分子特征与其三种常规配体（多奈哌齐、加兰他敏和美金刚）的分子特征进行比较，生成了预测这些化合物对 AChE 和 NMDA 生物活性的构效关系（SAR）模型。

结果

预测所考虑化合物生物活性的最相关描述符是溶剂可及表面积及其细分、疏水性、前沿分子轨道能量和芳环数以及可旋转键数。1,8-桉叶素是薄荷（Mentha spicata L. subsp. spicata）精油中的主要化合物，在疏水性（logP1,8-桉叶素=2.95，logPmemantine=2.81，logPdonepezil=4.11）、LUMO 能量（eLUMO1,8-桉叶素=3.01 eV，eLUMOmemantine=3.35 eV，eLUMOdonepezil=-0.35 eV）和所有疏水分子（SA_H1,8-桉叶素=350 Å2，SA_Hmemantine=358 Å2，SA_Hdonepezil=655 Å2）或极性原子（SA_P1,8-桉叶素=4 Å2，SA_Pmemantine=10 Å2，SA_Pdonepezil=44.62 Å2）的溶剂可及表面积方面，与美金刚相似，而与多奈哌齐不同。