Pharmacological Studies on 7-Hydroxymitragynine, Isolated from the Thai Herbal Medicine Mitragyna speciosa: Discovery of an Orally Active Opioid Analgesic

Pharmacological Studies on 7-Hydroxymitragynine,Isolated from the Thai Herbal Medicine

Mitragyna speciosa

:Discovery of an Orally Active Opioid Analgesic

Kenjiro Matsumoto2006

Contents

General Remarks 1Part

Ι

. Exploration of compounds acting on opioid receptors in components of

Mitragyna speciosa

and its related synthetic alkaloids1. Introduction 82. Materials and methods 83. Results 124. Discussion 17Part

ΙΙ

. Elucidation of opioid effect of 7-hydroxymitragynine and 9-hydroxycorynanthidine by

in vitro

assays1. Introduction 202. Materials and methods 203. Results 254. Discussion 30Part

ΙΙΙ

. Antinociceptive and side effects of 7-hydroxymitragynine in mice: Discovery of a potent and orally active opioid analgesic1. Introduction 352. Materials and methods 363. Results 404. Discussion 50Part IV. Effects of mitragynine on isolated tissues1. Introduction 562. Materials and methods 563. Results 614. Discussion 67Concluding Remarks 70References 72List of publications 79Acknowledgements 82

General Remarks

Substances derived from natural products have been utilized since the beginning of time for various medical purposes including the treatment of pain. Opium, for example, has been mentioned inthe earliest historical records, some 7000 years ago. In fact, research in the area of pain managementand drug addiction originally focused on natural products exclusively. Prototypical examples of suchnatural products are the opium poppy (

Papaver somniferum

). Morphine, an alkaloid component of theopium poppy, is the most widely used compound among narcotic analgesics and remains the goldstandard. Recently, analogs have been produced from natural substances, and completely syntheticcompounds based on natural pharmacophores have been introduced to the market. However, theresearch and medical fields still struggle with the undesirable side-effects of these analgesicsubstances (McCurdy and Scully 2005).Our research group has studied uniquely structured, nitrogen-containing compounds isolatedfrom the traditional Thai herb

Mitragyna speciosa

. This herb has long been used in tropical areas for its opium- and coca-like effects (Burkill, 1935). It has been used also as a substitute for opium and towean addicts off morphine (Grewal, 1932; Suwanlert, 1975). We have been investigating the pharmacological properties of this herb, individual components of its extracts, and structurally relatedcompounds since the 1980s. We compared the antinociceptive effects of

Mitragyna speciosa

andmitragynine, the major alkaloid of this herb, in

in vivo

experiments, and found that the antinociceptiveeffect of mitragynine was less potent than that of the crude extract of

Mitragyna speciosa

(Watanabeet al., 1992, 1999). This finding means that one or more minor constituents of

Mitragyna speciosa

may have a very potent antinociceptive effect. We have investigated mitragynine-related compoundsthat express interesting opioid activities: an oxidative derivative of mitragynine, mitragynine pseudoindoxyl, was found to exhibit potent opioid agonistic activity

in vitro

and antinociceptiveactivity

in vivo

(Yamamoto et al., 1999; Takayama et al., 2002). These findings prompted us toembark on the development of novel compounds based on the mitragynine skeleton, which is quitedifferent from the skeleton of morphine.In the present study attempting to find a new analgesic from the Thai herbal medicine, I surveyedthe opioid effects of the other constituents of

Mitragyna speciosa

and synthetic derivatives of 1