New Lycopodine-Type Alkaloids from Lycopodium carinatum.

The structures of new lycopodine-type alkaloids, lycopocarinamines A-F, which were isolated from Lycopodium carinatum, were elucidated by spectroscopic analysis and chemical conversions. The proposed structure of lycocarinatine A was revised.

Seven new monoterpenoid indole alkaloids from Gelsemium elegans.

Seven new indole alkaloids were isolated from the roots of Gelsemium elegans Benth. and their structures were determined by spectroscopic analysis and chemical transformation from known alkaloids. Kounaminal (1) is a new koumine-type alkaloid that contains an unusual aminal moiety. Humantenoxenine (2) and 15-hydroxyhumantenoxenine (3) are humantenine-type alkaloids that contain a novel ß-amino-α,ß-unsaturated ketone residue. The other four novel alkaloids are two gelsedilam-related and two gelsenicine-related alkaloids.

New iridoids from Gelsemium species.

Four new iridoids structurally related to gelsemide (5) were isolated from two Loganiaceous plants, Gelsemium elegans and G. rankinii. Among them, GEIR-1 (1) has a novel tetracyclic caged structure.

MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate], a derivative of the indole alkaloid mitragynine: a novel dual-acting mu- and kappa-opioid agonist with potent antinociceptive and weak rewarding effects in mice.

Mitragynine is a major indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that has opium-like properties, although its chemical structure is quite different from that of morphine. We attempted to develop novel analgesics derived from mitragynine, and thus synthesized the ethylene glycol-bridged and C10-fluorinated derivative of mitragynine, MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate]. We hypothesized that a dual-acting mu- and kappa-opioid agonist could produce potent antinociceptive effects with fewer rewarding effects compared with mu agonists. In this study, MGM-9 exhibited high affinity for mu- and kappa-opioid receptors with Ki values of 7.3 and 18 nM, respectively. MGM-9 showed a potent opioid agonistic effect, and its effects were meditated by mu- and kappa-opioid receptor mechanisms in in vitro assays. Subcutaneous and oral administration of MGM-9 produced potent antinociceptive effects in mouse tail-flick, hot-plate, and writhing tests. When administered orally, the antinociceptive effect of MGM-9 was seven to 22 times more potent than that of morphine. The antinociceptive effects of MGM-9 were mediated by both mu- and kappa-opioid receptors. Subcutaneous administration of MGM-9 twice daily for 5 days led to antinociceptive tolerance. In the gastrointestinal transit study, MGM-9 inhibited gastrointestinal transit, but its effect was weaker than that of morphine at equi-antinociceptive doses. Furthermore, MGM-9 induced less hyperlocomotion and fewer rewarding effects than morphine. The rewarding effect of MGM-9 was blocked by a mu antagonist and enhanced by a kappa antagonist. Taken together, the results suggest that MGM-9 is a promising novel analgesic that has a stronger antinociceptive effect and weaker adverse effects than morphine.

New procedure to mask the 2,3-pi bond of the indole nucleus and its application to the preparation of potent opioid receptor agonists with a Corynanthe skeleton.

Treatment of indole alkaloids with hypervalent iodine in the presence of ethylene glycol provides 2,3-ethylene glycol bridged adducts that could be converted into the original indoles under mild reductive conditions. This procedure, which involves masking of the reactivity of the indole nucleus at the beta-position, was utilized for the modification of the benzene ring of the indoline derivative and was applied to the preparation of potent opioid receptor agonists with the Corynanthe skeleton. [reaction: see text]

Involvement of mu-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa.

7-hydroxymitragynine, a constituent of the Thai herbal medicine Mitragyna speciosa, has been found to have a potent opioid antinociceptive effect. In the present study, we investigated the mechanism of antinociception and the inhibitory effect on gastrointestinal transit of 7-hydroxymitragynine, and compared its effects with those of morphine. When administered subcutaneously to mice, 7-hydroxymitragynine produced antinociceptive effects about 5.7 and 4.4 times more potent than those of morphine in the tail-flick (ED50=0.80 mg/kg) and hot-plate (ED50=0.93 mg/kg) tests, respectively. The antinociceptive effect of 7-hydroxymitragynine was significantly blocked by the mu1/mu2-opioid receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA) and the mu1-opioid receptor-selective antagonist naloxonazine in both tests. Thus, 7-hydroxymitragynine acts predominantly on mu-opioid receptors, especially on mu1-opioid receptors. Isolated tissue studies further supported its specificity for the mu-opioid receptors. Further, 7-hydroxymintragynine dose-dependently (ED50=1.19 mg/kg, s.c.) and significantly inhibited gastrointestinal transit in mice, as morphine does. The inhibitory effect was significantly antagonized by beta-FNA pretreatment, but slightly antagonized by naloxonazine. The ED50 value of 7-hydroxymitragynine on gastrointestinal transit was larger than its antinociceptive ED50 value. On the other hand, morphine significantly inhibits gastrointestinal transit at a much smaller dose than its antinociceptive dose. These results suggest that mu-opioid receptor mechanisms mediate the antinociceptive effect and inhibition of gastrointestinal transit. This compound induced more potent antinociceptive effects and was less constipating than morphine.

Four novel gelsenicine-related oxindole alkaloids from the leaves of Gelsemium elegans benth.

[reaction: see text] New types of four gelsenicine-related oxindole alkaloids were isolated from the leaves of Gelsemium elegans Benth. Gelsedilam (1) and 14-acetoxygelsedilam (2) are the first examples of 18,19-nor-type monoterpenoid indole alkaloids. Gelsefuranidine (3) and gelseiridone (4) have, respectively, an additional furan residue or an iridoid unit on the gelsenicine-related monoterpenoid indole alkaloid.

A new pimarane from Mitrephora tomentosa.

A new diterpenoid named (-)-8beta-hydroxypimar-15-en-18-oic acid was isolated, along with (-)-kaur-16-en-19-oic acid, 13,14-dihydrooropheic acid and beta-sitosterol, from the bark of Mitrephora tomentosa.