NEW MDMA Bioisosteres!

Summary

The 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

• 💊 MDMA has been granted breakthrough therapy status for its potential use in treating post-traumatic stress disorder (PTSD).
• 🏥 Despite the positive status, the FDA's advisory committee has voted against MDMA-assisted therapy, which may impact its approval in August 2024.
• 🔬 Research into new MDMA analogs is ongoing, with a recent paper discussing bioisosteric analogs that could offer improved safety and reduced side effects.
• 🔬🧪 Bioisosteric analogs are molecules where a functional group is replaced to maintain or improve potency and pharmacokinetic properties.
• 🧬 Metabolism of MDMA can lead to neurotoxicity and cytochrome P450 inhibition, causing potential drug interactions.
• 🧪 Researchers created benzoo analogs with substitutions of oxygen, sulfur, or selenium to address the issues related to MDMA metabolism.
• 🛠️ A simple two-step synthesis process was used to create these analogs, starting with a bromo-substituted bodol and a modified HEC reaction.
• 🧠 MDMA's effects are primarily through interactions with monoamine transporters, affecting neurotransmitter levels and influencing the body and mind.
• 🧪 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.
• 🔬 Molecular docking simulations revealed that the analogs maintained key interactions with transporters but had altered binding profiles.
• 🌟 A bioluminescence resonance energy transfer assay showed the analogs were less potent at 5-HT2 receptors, which could reduce side effects.
• 🧪 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

00:00

💊 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.

05:01

🔬 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.

Keywords

💡MDMA

MDMA, also known as ecstasy, is a psychoactive substance commonly associated with partying and raving. In the context of the video, it is highlighted for its potential therapeutic use, specifically for treatment-resistant post-traumatic stress disorder (PTSD). The script discusses the FDA's consideration of MDMA-assisted therapy and the challenges it faces in approval.

💡Breakthrough Therapy Status

This term refers to a designation given by the FDA to a drug that is intended to treat a serious condition and has shown substantial evidence of efficacy compared to available therapies. In the script, it is mentioned that MDMA was granted this status in 2017 for its use in treating PTSD, indicating its potential significance in the medical field.

💡Post-Traumatic Stress Disorder (PTSD)

PTSD is a mental health condition triggered by experiencing or witnessing a terrifying event. The script emphasizes that PTSD has limited treatment options and highlights the potential of MDMA-assisted therapy as a novel approach for treatment-resistant cases.

💡Bioisosteric Analogues

Bioisosteric analogues are molecules that have similar steric or electronic characteristics to another molecule, often used to improve pharmacokinetic properties while retaining or enhancing the potency of the original compound. The script discusses new MDMA bioisosteric analogues that may offer improved safety and reduced side effects.

💡Cytochrome P450

Cytochrome P450 is a group of enzymes involved in the metabolism of drugs and other substances in the body. The script explains that MDMA metabolites are formed through the action of these enzymes, which can lead to potential neurotoxicity and drug interactions.

💡Monoamine Transporters

These are proteins that transport monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, across cell membranes. The script describes how MDMA and its analogues interact with these transporters, affecting neurotransmitter levels and contributing to their psychoactive effects.

💡Reuptake

Reuptake refers to the process by which neurotransmitters are taken back up into the neuron that released them, ending their action. The script explains that MDMA and its analogues inhibit reuptake of certain neurotransmitters, leading to increased levels in the synaptic cleft.

💡Neurotoxicity

Neurotoxicity is the potential of a substance to cause damage to the nervous system. The script suggests that the metabolites of MDMA may be associated with neurotoxic effects, which is a concern in the context of its therapeutic use.

💡5-HT Receptors

5-HT receptors, also known as serotonin receptors, are a group of G-protein coupled receptors that respond to serotonin. The script discusses how MDMA interacts with subtypes of these receptors, potentially causing side effects such as hallucinogenic effects, cardiotoxicity, and appetite suppression.

💡Bioluminescence Resonance Energy Transfer (BRET)

BRET is a technique used to measure interactions between a molecule and a receptor by observing changes in light emission. The script describes how this method was used to assess the activity of the new MDMA analogues at the 5-HT receptors, providing insights into their potential side effects.

💡Metabolism

Metabolism in this context refers to the biochemical processes by which the body breaks down substances, including drugs. The script explains that the researchers investigated the metabolism of the new MDMA analogues to understand how they might be cleared from the body and to identify any potentially harmful metabolites.

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