<p><i>Mitragynina speciosa</i>, more commonly known as kratom, is a
plant native to Southeast Asia, the leaves of which have been used
traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently,
growing use of the plant in the United States and concerns that kratom
represents an uncontrolled drug with potential abuse liability, have
highlighted the need for more careful study of its pharmacological activity. The
major active alkaloid found in kratom, mitragynine, has been reported to have
opioid agonist and analgesic activity <i>in vitro</i>
and in animal models, consistent with the purported effects of kratom leaf in
humans. However, preliminary research has provided some evidence that
mitragynine and related compounds may act as atypical opioid agonists, inducing
therapeutic effects such as analgesia, while limiting the negative side effects
typical of classical opioids. Here we report evidence that an active metabolite
plays an important role in mediating the analgesic effects of mitragynine. We
find that mitragynine is converted <i>in
vitro </i>in both mouse and human liver preparations to the much more potent
mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is
mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine
is formed from mitragynine in mice and that brain concentrations of this
metabolite are sufficient to explain most or all of the opioid-receptor-mediated
analgesic activity of mitragynine. At the same time, mitragynine is found in the
brains of mice at very high concentrations relative to its opioid receptor
binding affinity, suggesting that it does not directly activate opioid
receptors. The results presented here provide a metabolism-dependent mechanism
for the analgesic effects of mitragynine and clarify the importance of route of
administration for determining the activity of this compound. Further, they
raise important questions about the interpretation of existing data on
mitragynine and highlight critical areas for further research in animals and
humans.</p>
<p><i>Mitragynina speciosa</i>, more commonly known as kratom, is a
plant native to Southeast Asia, the leaves of which have been used
traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently,
growing use of the plant in the United States and concerns that kratom
represents an uncontrolled drug with potential abuse liability, have
highlighted the need for more careful study of its pharmacological activity. The
major active alkaloid found in kratom, mitragynine, has been reported to have
opioid agonist and analgesic activity <i>in vitro</i>
and in animal models, consistent with the purported effects of kratom leaf in
humans. However, preliminary research has provided some evidence that
mitragynine and related compounds may act as atypical opioid agonists, inducing
therapeutic effects such as analgesia, while limiting the negative side effects
typical of classical opioids. Here we report evidence that an active metabolite
plays an important role in mediating the analgesic effects of mitragynine. We
find that mitragynine is converted <i>in
vitro </i>in both mouse and human liver preparations to the much more potent
mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is
mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine
is formed from mitragynine in mice and that brain concentrations of this
metabolite are sufficient to explain most or all of the opioid-receptor-mediated
analgesic activity of mitragynine. At the same time, mitragynine is found in the
brains of mice at very high concentrations relative to its opioid receptor
binding affinity, suggesting that it does not directly activate opioid
receptors. The results presented here provide a metabolism-dependent mechanism
for the analgesic effects of mitragynine and clarify the importance of route of
administration for determining the activity of this compound. Further, they
raise important questions about the interpretation of existing data on
mitragynine and highlight critical areas for further research in animals and
humans.</p>
<p>Mitragynine is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We developed a new synthetic method for selective functionalization of the unexplored C11 position of the mitragynine scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. We discovered that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. In the 7-hydroxymitragynine (7OH) series, the high efficacy parent compound was transformed to an equipotent low efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests after systemic administration. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.</p>
The dramatic increase in intensities of the higher-mass CsI cluster peaks suggests that sulfur acts as a laser-absorbing matrix for inorganic salts far superior to conventional matrices such as 2,5-dihydroxybenzoic acid and α-cyano-4-hydroxycinnamic acid.
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