Sulfobutylation of Beta-Cyclodextrin Enhances the Complex Formation with Mitragynine: An NMR and Chiroptical Study

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Mitragynine (MTR), the main indole alkaloid of the well-known plant kratom (Mitragyna speciosa) 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. Therefore, MTR and its derivatives became novel candidates for drug development. The poor aqueous solubility of MTR initiated the study of its host-guest complexation with beta-cyclodextrin (bCyD) and sulfobutylether-beta-cyclodextrin (SBEbCyD). Their intermolecular interactions were studied by chiroptical and NMR spectroscopy.

1H NMR titration studies revealed a weak binding (logb11 = 0.8) between MTR and bCyD, while in the case of SBEbCyD a much stronger interaction (logb11 = 3.68, logb21 = 6.87) and the co-existence of 1:1 and 2:1 MTR-SBEbCyD complexes was identified. Circular dichroism (CD) titration experiments (Kd = 206 mM, MTR∙SBEbCyD) were in good agreement with the NMR spectroscopic results. It was found that the sulfobutylation of the native bCyD significantly increases the stability of the supramolecular system due to the enlarged cavity, sidechain flexibility, and the possibility of host-guest electrostatic interaction under pH 4.5 conditions. Structure of the MTR-CyD complexes were also proposed based on CD and 1H-1H ROESY NMR data. Both techniques revealed the insertion of the indole moiety into the CyD cavity. This is the first in depth characterization of mitragynine – cyclodextrin system which serves a good entry point into the characterization and formulation studies of structurally related bioactive natural alkaloids found in kratom.

Suggested structure of the MTR∙SBEβCyD inclusion complex based on the registered 2D ROESY NMR spectra and the CD spectroscopic experiments.

Várnai, B.; Zsila, F.; Szakács, Z.; Garádi, Z.; Malanga, M.; Béni, S. Sulfobutylation of Beta-Cyclodextrin Enhances the Complex Formation with Mitragynine: An NMR and Chiroptical Study. Int. J. Mol. Sci. 202223, 3844. https://doi.org/10.3390/ijms23073844

Featured image credit: Wikipedia

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