Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary.
Center for Pharmacology and Drug Research & Development, Semmelweis University, H-1085 Budapest, Hungary.
Molecules. 2024 Nov 9;29(22):5302. doi: 10.3390/molecules29225302.
Mitragynine is an "atypic opioid" analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid-CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids.
美拉诺素是一种“非典型阿片类”镇痛药，具有独特的作用机制和良好的副作用特征。我们的目的是优化从辣木叶中提取生物碱的程序，并确定和分离最能穿透中枢神经系统的相关化合物。PAMPA-BBB 研究表明，美拉诺素及其共生物碱，即细叶美登木碱、美登普林和帕潘他丁，具有出色的体外 BBB 渗透性。我们采用 CPC、闪式色谱和制备 HPLC 方法的优化序列来分离出四种鉴定出的 BBB+生物碱。为了提高分离出的生物碱的生物利用度，我们通过亲和毛细管电泳研究了它们与环糊精（CD）的络合行为，使用了近 40 种 CD 衍生物。确定并比较了表观生物碱-CD 络合稳定常数，并进行了最相关的 CD 增溶度研究。中性和带负电荷的衍生物都能够与四种辣木生物碱形成复合物。结果表明，空腔大小、取代基类型和取代度也影响了复合物的形成。带负电荷的 Sugammadex、Subetadex 和磺基化-β-CD 类似物能够形成最稳定的复合物，超过 1000 M。这些结果为进一步研究辣木生物碱的溶解度和稳定性增强提供了良好的基础。
