Article by Murple regarding Kratom Alkaloids.
To read the full and in depth article on Kratom Alkaloids and more visit the link below.
Chemistry
Over 25 alkaloids have been isolated from kratom, most of which are yohimbe-type indoles and oxindoles. The most abundant alkaloids consist of three indoles and two oxindoles. The three indoles are mitragynine, paynanthine, and speciogynine - the first two of which appear to be unique to this species. The two oxindoles are mitraphylline and speciofoline. Other alkaloids present include other indoles and oxindoles such as ajmalicine, akuammigine, corynanthedine, mitraversine, rhynchophylline, speciociliatine (also unique to kratom) and stipulatine. Working with Malay plants, Houghton and Said found new types of indole alkaloids (mitragynaline, corynantheidaline, mitragynalinic acid, and corynantheidalinic acid), in very young leaves. Those alkaloids were reported as having an unusual skeleton, having a carbon function at the C14 position (compared with previously known monoterpenoid indoles), but Takayama et al. later revised the structure of mitragynaline and corynantheidaline, showing that there was no substitution on the 14 position.
Mitragynine is the most abundant alkaloid in the plant, and for this reason was long assumed to be the major chemical responsible for the effects of kratom. It was first isolated in 1907 by David Hooper, a process repeated in 1921 by E. J. Field, who gave the alkaloid its name. Its structure was first fully determined in 1964 by D. Zacharias, R. Rosenstein and E. Jeffrey. It was not until 1995 that H. Takayama et al. at Chiba University were able to synthetically produce mitragynine. It is structurally related to both the yohimbe alkaloids and voacangine. It is more distantly related to tryptamine-based psychedelic drugs such as psilocybin, ibogaine or LSD. Chemically, mitragynine is 9-methoxy-corynantheidine. It has the molecular formula C23H30N2O4 and a molecular weight of 398.49. Physically the freebase is a white, amorphous powder with a melting point of 102-106°C and a boiling point (bp5) of 230-240°C. It is soluble in alcohol, chloroform and acetic acid. The hydrochloride salt has a melting point of 243°C. It appears that it may be a fairly stable compound, as a mitragynine ethane disulphonate reference sample tested after fourteen years by TLC produced results not substantially different from fresh mitragynine picrate.
Alkaloid content varies from place to place and at different times, leading Shellard et al. in the 1970s to conclude that there may be different geographical variants within the species. Within each location, there is a quantitative variation in alkaloid content from month to month as well. The alkaloid content of the leaves of Mitragyna speciosa has been reported as 0.5% to 1.5% in dried leaf. An average leaf weighs about 1.7 grams fresh or 0.43 grams dried.
The Pharmacognosy Research Laboratories at Chelsea College collected thirty samples of kratom from Malaysia, Thailand, and Papua New Guinea between 1961 and 1970. All contained mitragynine, but beyond that there was considerable variation. The most common profile in Thai plants was mitragynine, speciogynine, speciociliatine, paynantheine, traces of ajmalicine, traces of (C9) methoxy-oxindoles, and traces of other indoles. This same profile was found in both red and green petioled plants. Other Thai plants contained different profiles, some with many more alkaloids. Of the Malay specimens, one contained mitragynine, speciofoline, and other indoles and oxindoles. The other contained mitragynine, ajmalicine, speciogynine, speciociliatine, paynantheine, traces of indoles, and (C9) methoxy-oxindoles. The Papua New Guinea specimen contained mitragynine, speciogynine, speciociliatine, paynantheine, specionoxeine, and isospecionoxeine.
Takayama et al. found that Thai and Malay kratom had in common the alkaloids mitragynine, speciogynine, speciociliatine, paynantheine and 7-hydroxymitragynine. In both samples, mitragynine was the most abundant alkaloid, but in the Thai kratom it made up 66% of the total alkaloid, while it made up only 12% of the alkaloids from the Malay sample. The Malay sample had mitragynaline and pinoresinol as major components, as well as mitralactonal, mitrasulgynine and 3,4,5,6-tetradehydromitragynine.
Beginning in the late 1990s, a group of researchers based out of Chiba University in Japan and Chulalongkorn University in Thailand began researching natural and synthetic analogues of mitragynine in search of new drugs with potential medicinal use. These studies have led to discoveries which have turned much of what was believed about kratom on its head. Results of a structure-activity relationship study published in 2002 helped to clarify the essential structural moieties in the Corynanthe type indole alkaloids required for opioid agonistic activity. Two oxidative derivatives of mitragynine, mitragynine pseudoindoxyl and 7-hydroxymitragynine, have been of particular interest.
Mitragynine pseudoindoxyl was first created in 1974 when a team of researchers led by Zarembo used the fungus Helminthosporum sp. to biotransform mitragynine and reported it to have 10 times the anti-nociceptive activity of mitragynine. A study conducted by the Japanese and Thai researchers previously mentioned has been found it to be a more potent analgesic than morphine by weight, and to act by way of mu and delta opioid receptors. Nevertheless, in a mouse tail-flick test, it demonstrated only weak anti-nociceptive activity compared to morphine.
More important is the research on 7-hydroxymitragynine (or mitragynine hydroxyindolenine), which is a naturally occurring minor alkaloid (around 2% of total alkaloids) first mentioned in a paper published in 1994. In a series of papers beginning in 2001, it has also been shown to be highly selective for mu receptors and is more potent by weight than morphine. Eventually, it occurred to the researchers that given the low potency of mitragynine, even though it is the most abundant alkaloid in the plant it can not account for the effects of kratom. Bioassays indicated that mitragynine was a much weaker anti-nociceptive than kratom extracts. Starting with crude extracts of kratom and moving then to five isolated alkaloids, it was found that 7-hydroxymitragynine is the most likely candidate for the chief agent of kratom's activity. It is thirty to forty-six times more potent than mitragynine and seventeen times more potent than morphine by weight. Antagonism by naloxone was used to confirm opioid-like activity of this alkaloid. Given that nearly all the chemical studies of kratom have been done on the assumption that mitragynine was the most important alkaloid, and that nearly all pharmacological research prior to the late 1990s was done on mitragynine or crude plant material, this discovery likely means that much of what we believe about kratom will need to be revised.
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