Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands.
Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compounds for mu-, delta-, and kappa-receptors were determined in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivatives of mitragynine, i.e., mitragynine pseudoindoxyl (2) and 7-hydroxymitragynine (12), were found as opioid agonists with higher potency than morphine in the experiment with guinea pig ileum. In addition, 2 induced an analgesic activity in the tail flick test in mice.
Mitragynine, an indole alkaloid from Thai folk medicine Mitragyna speciosa, exerts agonistic effects on opioid receptors. Gastric acid secretion is proposed to be regulated by opioid receptors in the central nervous system (CNS). Previously, we reported the dual roles (inhibition via micro-opioid receptors and stimulation via kappa-opioid receptors) of the opioid system in the central control of gastric acid secretion. We investigated whether mitragynine affects gastric acid secretion via opioid receptors in the CNS. Injection of mitragynine (30 microg) alone into the lateral cerebroventricle did not have a significant effect on basal gastric acid secretion in the perfused stomach of anesthetized rats. Injection of mitragynine (3-30 microg) into the fourth cerebroventricle, like morphine, inhibited 2-deoxy-D-glucose-stimulated gastric acid secretion. The inhibitory effect of mitragynine (30 microg) was reversed by naloxone (100 microg). These results suggest that mitragynine has a morphine-like action on gastric acid secretion in the CNS.
Reports of the various uses of Mitraynine in traditional medicine in the countries of the South East Asia region (Jansen & Prast, 1988; Suwanlert, 1974) spurred research into the
pharmacological aspects of its chemical constituents. More than twenty-five alkaloids have been identified from this plant (Ikram, 1885) but of these the major ones (in terms of % yield) are three indoles i.e. mitragynine, speciogynine and paynanthine and two oxindoles i.e. mitraphylline and speciofoline.
In a previous study (unpublished report) we had detected the analgesic property of the crude alkaloidal extract using the hot-plate method of Ankier (1974) and the tail-flick method of Sewell and Spencer (1976). The effect showed similarities to analgesia caused by morphine but its effect was not antagonized by Naloxone in the hot-plate test. This is interesting because although paracetamol also exhibited a significant effect in the hot tail-flick test, our additional experiment using the cold tail-flick test further separated the analgesic efficacy of the alkaloidal extract and morphine from that of paracetamol. The failure of paracetamol to exhibit antinociceptive effect in the cold tail-flick test suggests that analgesia induced by morphine and the extract is by a different pathway involving other mediators than that due to paracetamol. This test also showed that 5 mg/kg of morphine is about equipotent to 200mg/kg of the crude extract.
Other investigators have shown that the cold tail- flick method is a selective method able to screen centrally acting opiate-fike analgesic agents, and is not sensitive to analgesics acting peripherally, such as aspirin, or non-analgesic drugs acting on the central nervous system, such as chlorpromazine (Pizziketti et al., 1985).
By Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S.
Laboratory of Molecular Structure and Biological Function, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, 1-33, Inage-ku, Chiba 263-8522, Japan. firstname.lastname@example.org