68(P-51) タイ、マレーシア伝承薬物Mitragyna speciosa含有鎮痛性インドールアルカロイドに関する医薬化学的研究(ポスター発表の部)

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Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa Korth., 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 structure-activity relationship, and surveys of intrinsic activities and potencies on opioid receptors were studied, as follows. Initially, a variety of mitragynine derivatives were prepared, which included the modification of the substituent at C9 and of the indole nucleus. During this study, we found unusual dimerization reactions of indole alkaloid at C7, when phenyliodine (III) bis (trifluoroacetate) (PIFA) or Pb(OAc)_4, was used. This finding led us to develop a concise total synthesis of meso- and rac- chimonanthines (25 and 26). An indole alkaloid, mitragynaline, was first isolated from the young leaves of Malaysian Mitragyna speciosa Korth. and its chemical structure was proposed in 1991. In the present study, we concluded the structure of mitragynaline to be formula 28 by exhaustive NMR analysis at low temperature, by partial synthesis from mitragynine (1), and finally by X-ray analysis. Opioid agonistic activities of mitragynine-related compounds were evaluated by their ability to inhibit the electrically-induced twitch contraction with guinea-pig ileum preparation. Their affinities for μ,δ, and κ-receptors were determined in a receptor-binding assay. As the result, the essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were clarified. It was found that the methoxy group on the indole ring at the C9 position is essential structural function for opioid agonistic activity. Interestingly, with altering the functional group at the C9 position, i.e., OMe→OH→H, of mitragynine, the activities of compounds dramatically shifted from that of full agonists through partial agonists to that of antagonists on opioid receptors. Mitragynaline (28) was found to exhibit a potent antagonist for opioid receptors. The oxidative derivatives of mitragynine, i.e., 7-hydroxymitragynine (5) and mitragynine pseudoindoxyl (19), were found as opioid agonists with higher potency than morphine in experiment with guinea pig ileum. In addition, 5 induced a potent analgesic activity in the tail flick test in mice. Especially, this compound showed remarkable antinociceptive activity at oral administration in mice. In conclusion, we could find a promising lead-molecule for the development of new type of analgesics, which were structurally different from morphine.
天然有機化合物討論会の論文
2003-09-01

68(P-51) タイ、マレーシア伝承薬物Mitragyna speciosa含有鎮痛性インドールアルカロイドに関する医薬化学的研究(ポスター発表の部)

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