Medicinal Chemistry on Indole Alkaloids from Thai Medicinal Plants

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Mitragyna speciosa (Korth.) Havil., endemic to Malyasia and Thailand, is a species of particular medicinal importance. In these countries the leaves of this plant have been traditionally used such as a remedy as a stimulant, an anthelminic, a substitute for opium, an antidiarrheal or to relieve muscular pain. Phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia have lead to isolation and identification of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids. The first total synthesis of (-) -mitragynine (MG), the major component of this plant, was achieved in the optically pure form using an enantiomerically and stereochemically convergent route. Furthermore, the oxindole and pseudoindoxyl derivatives of mitragynine were prepared. Pharmacological evaluation of these natural and syntheic compounds was performed, which have lead to the following significant results. MG suppressed 5-HT2A receptor-mediated head-twitch responses in mi … More ce. This suppressive effect was antagonized by an alpha2-adrenoceptor antagonist, but not by noradrenaline- or 5-HT-depletors, suggesting that stimulation of postsynaptic alpha2-adrenoceptors and/or blockade of 5-HT2A receptors are involved in MG suppression of head-twitch responses. MG produced antinociception in the tail-pinch test in mice. MG-induced antinociception was attenuated not only by naloxone, an opioid antagonist, but also by alpha2-or5-HT-receptor antagonists. These results suggest that supraspinal opioid systems and descending monoaminergic systems play roles in antinociceptive activity of supraspinally administered MG on the mechanical noxious stimulation. Effects of MG on neurogenic contraction of vas deference and ileum were studied. MG inhibited neurotransmitter release from nerve endings, leading to inhibition of neurogenic contraction in vas deference. By using the patch clamp and the Ca fluorescent dye methods, MG was found to block L-and T-type Ca channel currents in neuronal cells. In the ileum, MG and mitragynine pseudoindoxyl (MGP) inhibited the neurogenic contraction through the stimulation of opioid mu-receptors. The opioid effects of MG and MGP were about 0.2-and 20-fold activity of morphine, respectively. These neuronal Ca channel blocking-and opioid-effects may be involved in the analgesic effect of MG. Less