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

Abstract

Ten indole and oxindole alkaloids (1–10) were isolated from the freshly collected leaves of Malaysian Mitragyna speciosa (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 (4) are reported herein for the first time. The spatial configuration of mitragynine oxindole B (4) was confirmed by single-crystal X-ray diffraction. Simultaneous quantification of the isolated alkaloids in the M. speciosa leaf specimens collected from different locations in the northern region of Peninsular Malaysia was also performed using UPLC-MS/MS. The oxindole alkaloids (1–4) and the indole alkaloid (10) were assessed for binding affinity at opioid receptors. Corynoxine (1) showed high binding affinity to μ-opioid receptors with a K i value of 16.4 nM. Further, corynoxine (1) 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 M. speciosa.

Comparative Toxicity Assessment of Kratom Decoction, Mitragynine and Speciociliatine Versus Morphine on Zebrafish (Danio rerio) Embryos

“…Mitragynine (1) and speciociliatine (2) were extracted and purified from the fresh M. speciosa leaves according to the method described in our previous study ( Chear et al, 2021 ). The detailed isolation procedures and spectroscopic data are provided in Supplementary Methods and Supplementary Figures S1–6 .…”

“…Kratom leaves contains more than 40 indole alkaloids and is reported to produce unique pharmacological effects through its complex synergistic or antagonistic interactions ( Obeng et al, 2020 ; Chear et al, 2021 ). Among these, mitragynine is the major alkaloid found in kratom leaves.…”

“…Among these, mitragynine is the major alkaloid found in kratom leaves. Other active alkaloids present in kratom leaves are 7-hydroxymitragynine, speciogynine, speciociliatine, and paynantheine ( Sharma et al, 2019 ; Chear et al, 2021 ). Mitragynine is known to reduce pain in preclinical evaluations ( Matsumoto et al, 1996 ; Carpenter et al, 2016 ).…”

Combinations of Indole based alkaloids fromMitragyna speciosa(Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines

“…Powdered dry leaves of M. speciosa (0.5 kg) was extracted using hot maceration method with 5 L of methanol at 45 °C for 3 consecutive days according to the procedures described (Chear et al, 2021). The suspension was filtered, and the supernatant was evaporated to dryness at 40 °C under reduced pressure to afford 150.0 g of crude extract.…”

“…F6 (0.5 g) was further purified on a medium size silica gel CC (5 x 40 cm) and eluted with a step gradient of ethyl acetate-methanol to afford speciociliatine (0.12 g) (2). Other major alkaloid standards -paynantheine (3) and speciogynine (4) were purified from F3 and F4, respectively by a silica gel flash chromatography (hexane-ethyl acetate, 90:10 to 20:80, v/v) (Chear et al, 2021). The chemical identity of each isolated compound was confirmed with the aid of 1 H & 13 C NMR, MS, and the spectroscopic data was then compared with those published data in literature (Sharma et al, 2019;Obeng et al, 2020).…”