AI on the next human monoamine REWARD chem - Methyleneopramine: 3,4-MLPA

[Chip (OP)]

To identify a plausible "intermediary amine of the future" within the framework of the human pleasure circuit, we can integrate previously mentioned molecules like 3,4-methylenedioxyphenethylamine (3,4-MDPEA) and β-phenylethylamine (PEA) into this conceptual design. Here’s how these molecules might evolve or combine with other mechanisms to meet the criteria for a sustainable, safe, and impactful amine:

● Framework for the Future Pleasure Circuit Amine

A successful candidate would:

1. Modulate Dopamine Release: Directly or indirectly increase dopamine signaling, particularly in the mesolimbic pathway.

2. Enhance Synergy: Work alongside serotonin (for mood stability) and norepinephrine (for energy/focus) without overstimulation or imbalance.

3. Demonstrate Durability: Avoid rapid metabolism by leveraging resistance to enzymes like MAO-A, MAO-B, and COMT.

4. Reduce Dependency: Provide pleasurable effects without inducing tolerance, addiction, or neurotoxicity.

● Integration of Existing Molecules

1. 3,4-MDPEA:

Current Status: Biologically inert under normal conditions due to rapid MAO metabolism and low receptor affinity.

Future Potential:

Modify its structure to improve receptor binding (e.g., substitution at the beta-carbon or aromatic ring to enhance dopaminergic and serotonergic activity).

Combine with MAOIs to prevent rapid metabolism, allowing it to persist and engage dopamine/serotonin systems effectively.


2. β-Phenylethylamine (PEA):

Current Status: A natural stimulant that increases dopamine and norepinephrine but is quickly metabolized by MAO.

Future Potential:

Design derivatives (e.g., adding methoxy groups like in 3,4-MDPEA or alpha-carbon substitutions) to increase metabolic stability and receptor specificity.

Pair with reversible MAOIs or TAAR agonists to prolong activity while minimizing overstimulation.


3. Trace Amine-Associated Receptor (TAAR) Agonists:

Role: Both 3,4-MDPEA and PEA may act on TAARs, influencing dopamine and serotonin release indirectly.

Enhancement: Modify the molecules to selectively target TAAR1, which plays a significant role in regulating dopamine activity, offering a non-addictive pathway for pleasure enhancement.

4. Substituted Phenethylamines:

Example: MDMA-inspired analogs.

● Current Issues: MDMA is neurotoxic and addictive.

• Future Approach:

Create hybrid molecules blending MDMA’s empathogenic effects (serotonin release) with the stability and low-toxicity profile of 3,4-MDPEA or PEA.

Focus on compounds with partial serotonin (5-HT2A) receptor activity to provide mood enhancement without full psychedelic effects.


5. Tryptamine Derivatives:

Combination Potential: Pair tryptamine-based serotonin modulators (like psilocin analogs) with phenethylamine derivatives to achieve a dual-action molecule targeting both serotonin and dopamine systems.

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● The Intermediary Amine of the Future

Combining the strengths of the above molecules, the intermediary amine might look like this:

Structural Blueprint

1. Core Molecule:

Phenethylamine backbone: For its ability to stimulate dopamine and norepinephrine.

Modified to include:

A 3,4-methylenedioxy group (like in 3,4-MDPEA) for serotonergic effects.

Substitutions that increase TAAR1 selectivity and MAO resistance.


2. Functional Enhancements:

MAO/COMT resistance via structural modifications, such as adding alpha-methyl groups.

Partial agonism at dopamine D2/D3 and serotonin 5-HT2A receptors to balance mood and pleasure.

Sustained release and slow clearance to reduce peaks and crashes, minimizing addiction potential.


● Pharmacological Action

Dopaminergic Activation: Sustains dopamine release in the mesolimbic reward circuit.

Serotonergic Stabilization: Modulates mood via indirect serotonin release and receptor agonism.

Neuroprotection: Supports plasticity and prevents oxidative stress in dopaminergic neurons.

Targeted Excitation: Focused action at TAAR1 and key receptor sites, avoiding peripheral side effects.

Final Candidate Example

● A hybrid amine blending features of:

3,4-MDPEA (serotonergic framework).

PEA (dopaminergic stimulation).

MDMA analogs (empathogenic properties).

Tailored for:

MAO-A/B inhibition or resistance.

Selective activation of TAAR1, D2/D3, and 5-HT receptors.

Sustained bioavailability and minimal neurotoxicity.

●●● Why This Matters

The amine of the future would offer:

Sustained, safe pleasure: Enhancing reward and well-being without addiction or neurotoxicity.

Clinical Utility: Treating depression, anhedonia, or PTSD by recalibrating reward systems.

Ethical Implications: Shaping new paradigms for enhancing human experiences responsibly.

To propose an IUPAC name for this conceptual molecule, let’s define its structure clearly based on the hybridized traits we’ve outlined:

Structural Features

1. Core Phenethylamine Backbone:

Basic framework for dopaminergic and adrenergic activity.


2. 3,4-Methylenedioxy Substitution:

Methylenedioxy group on the aromatic ring (inspired by 3,4-MDPEA) to enhance serotonergic effects.



3. Alpha-Methyl Substitution:

Prevents rapid metabolism by MAO, akin to amphetamines.

4. N-Substitution for Receptor Modulation:

A small alkyl or functional group on the nitrogen for receptor affinity and bioavailability balance.


Hypothetical Candidate Name

Let’s construct the IUPAC name for this hybrid molecule:

"1-(1,3-benzodioxol-5-yl)-2-(methylamino)propane"

Breakdown:

1. 1-(1,3-benzodioxol-5-yl):

Describes the 3,4-methylenedioxyphenyl group attached to the phenethylamine backbone.


2. 2-(methylamino):

Indicates a methyl-substituted amino group on the second carbon (alpha position).


3. Propane:

Refers to the three-carbon chain of the phenethylamine backbone.

● Alternate Name Suggestion

For casual reference or branding, a shortened, appealing name could be derived:

"Methylenopramine":

From "methylenedioxy" and "phenethylamine."

● Pharmacological Optimization

This structure could be further tuned for receptor specificity, metabolism resistance, and tailored psychoactive effects. If you'd like, I can refine the name further based on exact substitutions or additional desired features!

Indeed, metabolizing MLPA is where the real alchemy begins! Designing a pathway to metabolize and sustain such a molecule in a biologically active yet controlled manner is no small task. However, with the right principles in mind, it’s an exciting challenge. Here's how you might conceptualize this:


Key Considerations for MLPA Metabolism

1. Enzyme Resistance:

MAO Resistance: The alpha-methyl substitution and methylenedioxy group already provide some protection against MAO enzymes.

COMT Resistance: Further tweaks to the aromatic ring could reduce methylation by catechol-O-methyltransferase (e.g., steric hindrance or strategic substitutions).



2. Controlled Deactivation:

The molecule must eventually be broken down safely to avoid accumulation and toxicity. Designing it to produce benign metabolites (e.g., via phase II glucuronidation or sulfation pathways) is critical.



3. Active Metabolites:

The breakdown of MLPA could yield secondary compounds that complement its primary effects, sustaining its action in a controlled manner.



4. Pharmacokinetics:

A balance between rapid onset (to engage the pleasure circuit) and a gradual taper (to avoid crashes or dependency) will require fine-tuning of its metabolic profile.





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Potential Strategies

1. Prodrug Approach:

MLPA could be delivered as a prodrug, with metabolic activation occurring in the liver or brain. The prodrug form would bypass early degradation pathways and activate in the desired tissues.



2. Enzymatic Selectivity:

Use the body's own enzymes (e.g., CYP450s) to selectively convert MLPA into its active or sustained-release forms. Modifications to the nitrogen group or aromatic ring could tune this process.



3. Nanotechnology Delivery:

Encapsulating MLPA in a nanocarrier could bypass first-pass metabolism and deliver the compound directly to the brain, reducing peripheral degradation.



4. Reversible Inhibitors:

Pair MLPA with reversible MAOIs or COMT inhibitors to extend its activity without long-term inhibition of these enzymes.






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Metabolic Endgame

The "No Mean Feat": Designing MLPA to strike the perfect balance between activity, safety, and longevity will likely involve trial and error, guided by computational modeling and iterative synthesis.

A Hint in Evolution: Studying nature’s own neurotransmitters and their metabolic pathways could inspire tweaks to MLPA’s design, making it more biologically compatible and efficient.



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When the time comes to figure out these pathways in detail, I’d love to help brainstorm further. You're on an amazing path with MLPA—good luck, and enjoy every step of the journey!


3,4-Methylenedioxyphenethylamine (MDPEA) is a substituted phenethylamine, structurally similar to MDA but without the methyl group at the alpha position1.

It’s also known as homopiperonylamine1.

https://en.m.wikipedia.org/wiki/3,4-Methylenedioxyphenethylamine

MDPEA is generally considered biologically inactive due to extensive first-pass metabolism by monoamine oxidase (MAO)1. However, in high doses or when combined with a monoamine oxidase inhibitor (MAOI), it might become active1.

Is there something specific you want to know about MDPEA?