8 research outputs found
7âhydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects
Mitragynina speciosa, 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 in vitro
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 in
vitro 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
The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine
Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the Îź opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious Îź receptor agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce Îź receptor-dependent respiratory depression has not yet been studied. Experimental Approach: Respiration was measured in awake, freely moving, male CD-1 mice, using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally. Key Results: The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10 mg¡kgâ1 produced the same level of effect. In contrast, 7-OH mitragynine induced a dose-dependent effect on mouse respiration. At equi-depressant doses, both mitragynine and 7-OH mitragynine induced prolonged anti-nociception. Inhibition of CYP3A reduced mitragynine-induced respiratory depression and anti-nociception without affecting the effects of 7-OH mitragynine. Conclusions and Implications: Both the anti-nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced respiratory depression. These data suggest that such âmetabolic saturationâ at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic
Site selective CâH functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy
Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy
Constructing <i>Iboga</i> Alkaloids via CâH Bond Functionalization: Examination of the Direct and Catalytic Union of Heteroarenes and Isoquinuclidine Alkenes
The <i>iboga</i> alkaloids
have attracted considerable
attention in both the scientific community and popular media due to
their reported ability to reverse or markedly diminish cravings for,
and self-administration of, the major drugs of abuse. We have developed
three new intramolecular CâH functionalization procedures leading
to the core seven-membered ring of the <i>iboga</i> skeleton,
a cyclization that proved to be highly challenging. The electrophilic
palladium salt PdÂ(CH<sub>3</sub>CN)<sub>4</sub>(BF<sub>4</sub>)<sub>2</sub> was effective for the cyclization of diverse <i>N-</i>(2-arylethyl)Âisoquinuclidines with yields of 10â35%. A two-step,
bromination-reductive Heck reaction protocol was also effective for
the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed
CâH functionalization provided the benzofuran analogues of
ibogamine (74%) and <i>epi</i>-ibogamine (38%). Although
each approach suffers from significant shortcomings, in combination,
the methods described provide practical routes to diverse ibogamine
analogues
Assessment of the potential of novel and classical opioids to induce respiratory depression in mice
Synthetic and Receptor Signaling Explorations of the <i>Mitragyna</i> Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
Mu-opioid receptor
agonists represent mainstays of pain management.
However, the therapeutic use of these agents is associated with serious
side effects, including potentially lethal respiratory depression.
Accordingly, there is a longstanding interest in the development of
new opioid analgesics with improved therapeutic profiles. The alkaloids
of the Southeast Asian plant <i>Mitragyna speciosa</i>,
represented by the prototypical member mitragynine, are an unusual
class of opioid receptor modulators with distinct pharmacological
properties. Here we describe the first receptor-level functional characterization
of mitragynine and related natural alkaloids at the human mu-, kappa-,
and delta-opioid receptors. These results show that mitragynine and
the oxidized analogue 7-hydroxymitragynine, are partial agonists of
the human mu-opioid receptor and competitive antagonists at the kappa-
and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine
are G-protein-biased agonists of the mu-opioid receptor, which do
not recruit β-arrestin following receptor activation. Therefore,
the <i>Mitragyna</i> alkaloid scaffold represents a novel
framework for the development of functionally biased opioid modulators,
which may exhibit improved therapeutic profiles. Also presented is
an enantioselective total synthesis of both (â)-mitragynine
and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed
MannichâMichael reaction sequence as the key transformation.
Pharmacological evaluation of (+)-mitragynine revealed its much weaker
opioid activity. Likewise, the intermediates and chemical transformations
developed in the total synthesis allowed the elucidation of previously
unexplored structureâactivity relationships (SAR) within the <i>Mitragyna</i> scaffold. Molecular docking studies, in combination
with the observed chemical SAR, suggest that <i>Mitragyna</i> alkaloids adopt a binding pose at the mu-opioid receptor that is
distinct from that of classical opioids