9 research outputs found
7‑hydroxymitragynine 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
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A minimalist biosensor: Quantitation of cyclic di-GMP using the conformational change of a riboswitch aptamer.
Cyclic di-GMP (c-di-GMP) is a second messenger that is important in regulating bacterial physiology and behavior, including motility and virulence. Many questions remain about the role and regulation of this signaling molecule, but current methods of detection are limited by either modest sensitivity or requirements for extensive sample purification. We have taken advantage of a natural, high affinity receptor of c-di-GMP, the Vc2 riboswitch aptamer, to develop a sensitive and rapid electrophoretic mobility shift assay (EMSA) for c-di-GMP quantitation that required minimal engineering of the RNA
A minimalist biosensor: Quantitation of cyclic di-GMP using the conformational change of a riboswitch aptamer
<div><p>Cyclic di-GMP (c-di-GMP) is a second messenger that is important in regulating bacterial physiology and behavior, including motility and virulence. Many questions remain about the role and regulation of this signaling molecule, but current methods of detection are limited by either modest sensitivity or requirements for extensive sample purification. We have taken advantage of a natural, high affinity receptor of c-di-GMP, the Vc2 riboswitch aptamer, to develop a sensitive and rapid electrophoretic mobility shift assay (EMSA) for c-di-GMP quantitation that required minimal engineering of the RNA.</p></div
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 (−)-mitragynine
and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed
Mannich–Michael 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 structure–activity 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
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 (−)-mitragynine
and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed
Mannich–Michael 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 structure–activity 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
7-Hydroxymitragynine 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
Deconstructing the <i>Iboga</i> Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound
Modulation of growth factor signaling
pathways in the brain represents
a new experimental approach to treating neuropsychiatric disorders
such as depression, anxiety, and addiction. Neurotrophins and growth
factors exert synaptic, neuronal, and circuit level effects on a wide
temporal range, which suggests a possibility of rapid and lasting
therapeutic effects. Consequently, identification of small molecules
that can either enhance the release of growth factors or potentiate
their respective pathways will provide a drug-like alternative to
direct neurotrophin administration or viral gene delivery and thus
represents an important frontier in chemical biology and drug design.
Glial cell line-derived neurotrophic factor (GDNF), in particular,
has been implicated in marked reduction of alcohol consumption in
rodent addiction models, and the natural product ibogaine, a substance
used traditionally in ritualistic ceremonies, has been suggested to
increase the synthesis and release of GDNF in the dopaminergic system
in rats. In this report, we describe a novel <i>iboga</i> analog, XL-008, created by unraveling the medium size ring of the
ibogamine skeleton, and its ability to induce release of GDNF in C6
glioma cells. Additionally, XL-008 potentiates the release of GDNF
induced by fibroblast growth factor 2 (FGF2), another neurotrophin
implicated in major depressive disorder, increasing potency more than
2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and
efficacy more than 3-fold. The GDNF release by both XL-008 and the
FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K
signaling pathways but not through PLCγ in C6 glioma cells