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.