Exploring the Chemistry of Alkaloids from Malaysian <i>Mitragyna speciosa</i> (Kratom) and the Role of Oxindoles on Human Opioid Receptors

Abstract

Ten indole and oxindole alkaloids (<b>1</b>-<b>10</b>) were isolated from the freshly collected leaves of Malaysian <i>Mitragyna speciosa</i> (Kratom). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data analysis. The spectroscopic data of mitragynine oxindole B (<b>4</b>) are reported herein for the first time. The spatial configuration of mitragynine oxindole B (<b>4</b>) was confirmed by single-crystal X-ray diffraction. Simultaneous quantification of the isolated alkaloids in the <i>M. speciosa</i> leaf specimens collected from different locations in the northern region of Peninsular Malaysia was also performed using UPLC-MS/MS. The oxindole alkaloids (<b>1</b>-<b>4</b>) and the indole alkaloid (<b>10</b>) were assessed for binding affinity at opioid receptors. Corynoxine (<b>1</b>) showed high binding affinity to μ-opioid receptors with a <i>K</i>_<i>i</i> value of 16.4 nM. Further, corynoxine (<b>1</b>) was 1.8-fold more potent than morphine in rats subjected to a nociceptive hot plate assay. These findings have important implications for evaluating the combined effects of the minor oxindole alkaloids in the overall therapeutic activity of <i>M. speciosa</i>.