NEW MDMA Bioisosteres!
Summary
TLDRThe script discusses the evolving perception of MDMA, beyond partying, toward its potential therapeutic use, particularly for treatment-resistant PTSD. Despite the FDA's advisory committee voting against MDMA-assisted therapy, ongoing research into bioisosteric analogs suggests these compounds could offer improved safety and reduced side effects. The analogs retain activity on monoamine transporters but show less potency at 5-HT2 receptors, potentially reducing side effects. The study also indicates better metabolic profiles for these analogs, which warrant further behavioral and metabolite studies.
Takeaways
- π MDMA has been granted breakthrough therapy status for its potential use in treating post-traumatic stress disorder (PTSD).
- π₯ Despite the positive status, the FDA's advisory committee has voted against MDMA-assisted therapy, which may impact its approval in August 2024.
- π¬ Research into new MDMA analogs is ongoing, with a recent paper discussing bioisosteric analogs that could offer improved safety and reduced side effects.
- π¬π§ͺ Bioisosteric analogs are molecules where a functional group is replaced to maintain or improve potency and pharmacokinetic properties.
- 𧬠Metabolism of MDMA can lead to neurotoxicity and cytochrome P450 inhibition, causing potential drug interactions.
- π§ͺ Researchers created benzoo analogs with substitutions of oxygen, sulfur, or selenium to address the issues related to MDMA metabolism.
- π οΈ A simple two-step synthesis process was used to create these analogs, starting with a bromo-substituted bodol and a modified HEC reaction.
- π§ MDMA's effects are primarily through interactions with monoamine transporters, affecting neurotransmitter levels and influencing the body and mind.
- π§ͺ The new analogs were tested in cells and showed similar activity to MDMA at the monoamine transporters but were less potent at 5-HT2 receptors.
- π¬ Molecular docking simulations revealed that the analogs maintained key interactions with transporters but had altered binding profiles.
- π A bioluminescence resonance energy transfer assay showed the analogs were less potent at 5-HT2 receptors, which could reduce side effects.
- π§ͺ In vitro metabolism studies indicated that the analogs did not form harmful intermediates like MDMA, suggesting improved safety.
Q & A
What is the primary reason for the recent news about MDMA?
-MDMA has been in the news primarily for its potential use in treating treatment-resistant post-traumatic stress disorder (PTSD), having been granted breakthrough therapy status in 2017.
What is the FDA's decision regarding MDMA-assisted therapy as of the script's mention?
-As of the script's mention, the FDA's advisory committee has voted against MDMA-assisted therapy, which could reduce the chance of its approval.
What are bioisosteric analogs and how do they relate to MDMA?
-Bioisosteric analogs are molecules where a functional group is replaced with one that has similar steric or electronic characteristics to improve pharmacokinetic properties while retaining or improving potency. New research has reported bioisosteric analogs of MDMA that may have improved safety and reduced side effects.
What is the significance of the methylene dioxy ring in MDMA and its metabolism?
-The methylene dioxy ring in MDMA is metabolized by cytochrome P450 enzymes, leading to the formation of a catechol species, which can cause potential neurotoxicity and cytochrome P450 inhibition, leading to drug-drug interactions.
How did the researchers create the benzoo analogs of MDMA?
-The researchers created the benzoo analogs by substituting the free position of the benzene ring with either oxygen, sulfur, or selenium. They used a simple two-step synthesis process involving a modified HEC reaction and reductive amination.
What role do monoamine transporters play in the effects of MDMA?
-Monoamine transporters are responsible for transferring neurotransmitters like serotonin, dopamine, and norepinephrine across membranes, regulating their levels. MDMA acts as a substrate of these transporters, inhibiting the reuptake and stimulating the release of these neurotransmitters, leading to increased extracellular levels.
How were the new analogs tested for their activity on monoamine transporters?
-The new analogs were tested in cells expressing the monoamine transporters to compare their activity to MDMA. The tests showed that both MDMA and the analogs were low micromolar inhibitors of each transporter, indicating retained activity.
What technique did the researchers use to test the analogs' interaction with the 5-HT2 receptors?
-The researchers used bioluminescence resonance energy transfer (BRET) to test the activity of the analogs at the 5-HT2 receptors, which measures the interaction between the analogs and the receptor by observing changes in light emission.
What are the potential side effects of MDMA associated with its activity at the 5-HT2 receptors?
-MDMA's activity at the 5-HT2A receptor is believed to cause its hallucinogenic effects, while its activity at the 5-HT2B receptor is thought to cause cardiotoxicity issues. Its effects at the 5-HT2C receptor appear to decrease appetite.
How did the researchers assess the metabolism of the new MDMA analogs?
-The researchers used an in vitro system with human liver microsomes and cytochrome P450 to replicate liver metabolism. They incubated the compounds in this environment and identified the metabolites using high-resolution mass spectrometry.
What were the findings regarding the metabolism and clearance of the new analogs compared to MDMA?
-The study found that the analogs did not form any catechol-like intermediates like MDMA, and showed similar clearance levels for the oxygen and selenium analogs when compared to MDMA. However, the sulfur analog had a faster clearance, although the reasons are not completely clear.
Outlines
π MDMA's Therapeutic Potential and Challenges
The script discusses the public perception of MDMA as a party drug and its emerging role in treating post-traumatic stress disorder (PTSD). It mentions that MDMA was granted breakthrough therapy status in 2017 for its potential in treatment-resistant PTSD, but the advisory committee has voted against MDMA-assisted therapy, which may affect its FDA approval in August 2024. The script also introduces research into new bioisosteric analogs of MDMA, which aim to improve safety and reduce side effects by altering the methylene dioxy ring. These analogs were tested for their effects on monoamine transporters and serotonin receptors, showing promising results in maintaining therapeutic activity while potentially reducing neurotoxicity and drug interactions.
π¬ Exploring Bioisosteric Analogs for Improved MDMA Safety
This paragraph delves into the specifics of bioisosteric analogs of MDMA, focusing on their synthesis and testing for activity. The analogs, which replace the methylene dioxy ring with oxygen, sulfur, or selenium, were synthesized using a two-step process involving a modified HEC reaction. The analogs were found to be low micromolar inhibitors of monoamine transporters and to stimulate neurotransmitter release, similar to MDMA. Molecular docking simulations and bioluminescence resonance energy transfer assays were used to compare the binding of these analogs to MDMA. The analogs showed reduced potency at serotonin 5-HT2 receptors, which could lead to fewer side effects. In vitro metabolism studies using human liver microsomes indicated that the analogs do not form catechol-like intermediates, suggesting improved metabolic stability. The sulfur analog demonstrated faster clearance, although the reasons are unclear. The study concludes that these findings warrant further investigation into the analogs' behavioral effects and metabolite profiles.
Mindmap
Keywords
π‘MDMA
π‘Breakthrough Therapy Status
π‘Post-Traumatic Stress Disorder (PTSD)
π‘Bioisosteric Analogues
π‘Cytochrome P450
π‘Monoamine Transporters
π‘Reuptake
π‘Neurotoxicity
π‘5-HT Receptors
π‘Bioluminescence Resonance Energy Transfer (BRET)
π‘Metabolism
Highlights
MDMA was granted breakthrough therapy status in 2017 for its use in treatment-resistant post-traumatic stress disorder.
The FDA's advisory committee voted against MDMA-assisted therapy ahead of the FDA's decision for its approval in August 2024.
Research into new MDMA analogs has been ongoing, with a focus on improved safety and reduced side effects.
Bioisosteric analogs are molecules with similar steric or electronic characteristics, aiming to improve pharmacokinetic properties.
MDMA's major metabolite in humans is associated with potential neurotoxicity and cytochrome P450 inhibition.
Researchers created benzoo analogs of MDMA to address issues related to metabolism and side effects.
A simple two-step synthesis process was used to create the benzoo analogs with substitutions of oxygen, sulfur, or selenium.
MDMA and its analogs were tested as low micromolar inhibitors of monoamine transporters.
Molecular docking simulations were conducted to compare the binding of analogs to MDMA at monoamine transporters.
MDMA primarily acts on monoamine transporters, influencing neurotransmitter levels and affecting the body and mind.
The new analogs were found to be approximately 10-fold less potent at 5-HT2 receptors than MDMA, potentially reducing side effects.
Bioluminescence resonance energy transfer was used to measure the interaction between analogs and the 5-HT2 receptors.
The analogs showed similar clearance levels to MDMA but did not form any catechol-like intermediates.
The sulfur analog demonstrated faster clearance, although the reasons are not completely clear.
The study suggests that bioisosteric replacements of the methylene dioxy ring in MDMA could improve safety and reduce side effects.
Further behavioral studies in rodents and research on the metabolites of these analogs are recommended.
The research provides insights into the development of safer and more effective MDMA analogs for therapeutic use.
Transcripts
when most people hear about MDMA they
think about partying or raving but
recently MDMA has been in the news for
other
reasons in 2017 MDMA was granted
breakthrough therapy status for its use
in treatment resistant post-traumatic
stress disorder a condition with limited
treatment
options however ahead of the fda's
decision for its approval in August 2024
the advisory committee has voted against
MDMA assisted therapy which could reduce
the chance of its
approval while phase three clinical
trials have been completed Research into
new analoges of MDMA has been on going a
new research paper published just two
weeks after the adviser committee's
meeting has reported new bioisosteric
analoges of MDMA which may have improved
safety and reduced side effects
bioisosteric analoges are molecules
where a functional group has been
replaced with one that has similar
steric or electronic characteristics
this is done to improve pharmokinetic
properties while retaining or improving
potency at the desired
Target for example in a previous video
we saw how the molecule cubane acts as a
bioisostere of fenal rings in known
Pharmaceuticals improving metabolic
stability and
solubility for MDMA the major metabolite
in humans results from the metabolism of
the methylene dioxy ring by cytochrome
p450 enzymes the ring is opened for a
carbine intermediate to form a catacol
species which can go on to react
further this creates two problems
firstly MDMA metabolites have been the
proposed cause of the potential
neurotoxicity associated with its use
secondly MDMA and its metabolites are
cytochrome p450 Inhibitors which can
lead to drug drug
interactions this team of researchers
looked at using bioisosteric analogs of
the methylene dioxy phen ring to address
these
issues they created three different
benzoo analoges where the free position
is substituted with either oxygen sulfur
or
selenium to make these molecules a
simple synthesis of only two steps was
used they started with the relevant
bodol substituted in the five position
with a bromine
substituent they used this in a modified
HEC reaction
in which isopren acetate is reacted with
tribu Timo oxide and a padium catalytic
system in this reaction tribu Timo oxide
first activates the isoprenol acetate
turning it into a more effective
nucleophile a standard HEC reaction can
then occur with hydrolysis of the enol
leading to the Ketone product a
reductive amination with methy amine and
sodium tric toxy borohydride leads to
the final
product there is strong evidence that
MDMA exhibits the majority of its
effects through interactions with the
mono aiming Transporters of which there
are three major types serotonin dopamine
and
norepinephrine the role of these
proteins is to transfer these
neurotransmitters across membranes
regulating intra and extracellular
levels of these free key
neurotransmitters more specifically they
are Prim involved in the reuptake of
these molecules from outside neurons
which is a vital part of
neurotransmission and has a huge impact
on the body due to this they are the
target of many pharmaceutical compounds
as well as recreational
drugs mtma acts as a substrate of these
proteins inhibiting the reuptake of
these
neurotransmitters in addition to this
MDMA also stimulates the release of
these neurotransmitters by reversing the
flow of these molecules through their
Transporters these two effects lead to
increased extracellular levels of these
neurotransmitters which can then go on
to bind to their relevant receptors and
alter the body and
mind these new analoges were tested in
cells expressing these Transporters to
compare their activity to
MDMA these tests showed that MDMA and
these analoges were all low microma
Inhibitors of each transporter showing
that these changes retain activity at
these key
receptors further tests were used to
show that these analoges also stimulate
the release of these
neurotransmitters to complement this
data the researchers carried out
molecular docking simulations to see how
The Binding of these analoges compared
to
MDMA they started with the docking of
these molecules to the serotonin
monoamine transporter and as expected
similar interactions are observed in
this case the positively charged amino
group interacts by hydrogen bonds with
the aspartate 98 and the serin 438
residues when looking at the dopamine
transporter the same interactions are
conserved with respect to
MDMA however this time additional
aromatic stacking interactions can be
formed between the aromatic dzur ring
and the tyrosine 156
residue while MDMA primarily acts on
mono aiming Transporters it also has
interactions at a subtype of Serotonin
receptor
these interactions are thought to cause
some of the side effects associated with
MDMA
use it weak binding at the 5 ht2a
receptor is believed to cause its small
hucog enic effects while its activity at
the 5 ht2 b receptor is thought to cause
the cardiotoxicity issues associated
with its use its effects at the 5 ht2 C
receptor appear only to decrease
appetite the five HT receptors are
g-coupled protein receptors
to test the activity of these analoges
the researchers used an interesting
technique called bioluminescence
resonance energy transfer in this assay
a decrease in light emitted from the
acceptor protein is observed when the
beta subunit is released this is due to
an increase in distance between the two
proteins which reduces the energy
transfer this only occurs when the
receptor protein is activated Through
The Binding of a molecule so can be used
to measure the interaction between the
analoges and the
receptor this assay revealed that all
three of these analogs were
approximately 10 fold less potent at
these receptors than MDMA which could
lead to reduced side
effects finally tests were carried out
to see if The bioisosteric Replacements
of the methylene dioxy ring stopped
metabolism at this position the
researchers used an invitro system to
replicate metabolism by the liver they
did this by using human liver microsomes
combined with cyoo
the compounds were then incubated in
this environment and the metabolites
were identified using high resolution
Mass spectrometry n dilation was the
only common metabolite between MDMA and
the analogs
tested n Hydrox silation also occurred
for the benzo diazo analogs importantly
these analoges do not form any catacol
like intermediates like
MDMA this data shows similar clearance
levels for omda and S dma when compared
to
MDMA however the sulfur analog had a
faster clearance for reasons that are
not completely clear this study was the
first of its kind to look at novel
bioisosteric Replacements of the
methylene dioxy ring these bioisosteric
Replacements appear to have a similar
effect to MDMA on the mono aiming
Transporters But A reduced effect at the
5 ht2
receptors this change as well as the
improved metabolism of these compounds
could reduce the side effects and
improve the safety of these molecules
compared to
MDMA the researchers comment that this
data justifies more studies around these
compounds particularly Behavioral
Studies in rodents and further studies
on the metabolites of these
analoges let me know what you think
about these new molecules and the fda's
upcoming
decision if you're interested in
learning more about bio isos check out
this video where I discussed the use of
cubane in known Pharmaceuticals and
drugs
Browse More Related Video
Antiepileptics: Nursing Pharmacology
Taurine: The Nutrient of Youth [Science Explained]
Topical Finasteride For Hair Loss: How to Use and Where To Get It
Top 5 Benefits Of Castor Oil For Face | Dermatologist Explains
Seeking βbetter solutions,β some veterans eye psychedelics to treat PTSD
Does Red Light Therapy stimulate Mitochondria? Not always...
5.0 / 5 (0 votes)