Department of Pharmacognosy, Semmelweis University, Üllői út. 26, H-1085 Budapest, Hungary.
Research Centre for Natural Sciences, Institute of Materials and Environmental Chemistry, H-1117 Budapest, Hungary.
Int J Mol Sci. 2022 Mar 31;23(7):3844. doi: 10.3390/ijms23073844.
Mitragynine (MTR), the main indole alkaloid of the well-known plant (), is one of the most studied natural products nowadays, due to its remarkable biological effects. It is a partial agonist on the opioid receptors, and as such relieves pain without the well-known side-effects of the opioids applied in the clinical practice. MTR and its derivatives therefore became novel candidates for drug development. The poor aqueous solubility and low bioavailability of drugs are often improved by cyclodextrins (CyDs) as excipients through host-guest type complex formation. Among the wide variety of CyDs, sulfobutylether-beta-cyclodextrin (SBEβCyD) is frequently used and official in the European and U.S. Pharmacopoeia. Herein, the host-guest complexation of MTR with βCyD and SBEβCyD was studied using chiroptical and NMR spectroscopy. It was found by NMR measurements that MTR forms a rather weak (log = 0.8) 1:1 host-guest complex with βCyD, while the co-existence of the 2MTR∙SBEβCyD and MTR∙SBEβCyD species was deducted from H NMR titrations in the millimolar MTR concentration range. Sulfobutylation of βCyD significantly enhanced the affinity towards MTR. The structure of the formed inclusion complex was extensively studied by circular dichroism spectroscopy and 2D ROESY NMR. The insertion of the indole moiety was confirmed by both techniques.
标题：基于圆二色光谱和二维 ROESY NMR 研究美托拉宗与 β-环糊精和磺丁基醚-β-环糊精的主客体包合作用
摘要：美托拉宗（MTR）是著名植物（）中的主要吲哚生物碱，由于其显著的生物学效应，是当今研究最多的天然产物之一。它是阿片受体的部分激动剂，因此可以缓解疼痛，而没有临床应用的阿片类药物所熟知的副作用。MTR 及其衍生物因此成为药物开发的新候选物。药物的水溶性差和生物利用度低通常可以通过环糊精（CyD）作为赋形剂通过主客体型络合作用来改善。在各种 CyD 中，磺丁基醚-β-环糊精（SBEβCyD）经常被用作欧洲和美国药典中的赋形剂。在此，使用圆二色光谱和 NMR 光谱研究了 MTR 与βCyD 和 SBEβCyD 的主客体络合作用。通过 NMR 测量发现，MTR 与βCyD 形成相当弱的（log = 0.8）1:1 主客体络合物，而从毫摩尔 MTR 浓度范围内的 H NMR 滴定中推断出存在 2MTR·SBEβCyD 和 MTR·SBEβCyD 两种物质共存。βCyD 的磺丁基化显著增强了对 MTR 的亲和力。通过圆二色光谱和二维 ROESY NMR 广泛研究了形成的包合复合物的结构。两种技术都证实了吲哚部分的插入。
