Kratom Alkaloids: A Blood–Brain Barrier Specific Membrane Permeability Assay-Guided Isolation and Cyclodextrin Complexation Study
András Dohárszky,
Erika Mária Vági,
Árpád Könczöl,
Alexandra Simon,
Erzsébet Várnagy,
Miras Muratov,
Kristóf István Steiger,
Bianka Várnai,
Szabolcs Béni,
Eszter Riethmüller,
Ida Fejős
Affiliations
András Dohárszky
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Erika Mária Vági
Department of Chemical and Environmental Process Engineering, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, H-1111 Budapest, Hungary
Árpád Könczöl
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Alexandra Simon
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Erzsébet Várnagy
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Miras Muratov
Department of Chemical and Environmental Process Engineering, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, H-1111 Budapest, Hungary
Kristóf István Steiger
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Bianka Várnai
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Szabolcs Béni
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Eszter Riethmüller
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
Ida Fejős
Department of Pharmacognosy, Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary
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−1. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids.
