The Challenge : Design a Dopamine Releasing Agent.

[MedicinalUser247]

The challenge is simple. Design a Dopamine agonist that doesn't effect Norepinephrine in the body. All people are welcome to this challenge including Drop outs all the way up to having a PHD. This challenge has no time limit. So, if you want to take years figuring it out you can.

p.s. The Dopamine agonist you design must have to at least be able to get you High.

 

[streaM Freak]

I guess I'd ask myself, is there "reward" in not "fighting"?

 

[MedicinalUser247]

This is my Design. -> https://ibb.co/nM5s7yDM I'd like to see if you could Design something better.

 

[neversickanymore]

N&Pd?

 

[4DQSAR]

Sci-Hub. Trishomocubane as a scaffold for the development of selective dopamine transporter (DAT) ligands / Bioorganic & Medicinal Chemistry Letters, 2011

Compound 12.

Now to be clear, this is a SINGLE reference and used rat as their model. Famously rats demonstrate 'ratatonia' regardless of if they are given a stimulant, depressent, psychedelic or other.

In this case a microtome was used to section the brains of rats that had been sacrificed.

I feel the MOST useful finding is that one of the four stereoisomers (1S,2S,4R) of fencamfamine MAY be a simpler selective dopamine releaser. But I checked and as yet nobody has succeeded in resolving the four stereoisomers of fencamfamine. Even the improved synthesis does not allow a single isomer to be produced. So we cannot confirm that fact, let alone make it at scale - unless a even newer synthesis is known.

Trishomocubanes: novel σ-receptor ligands modulate amphetamine-stimulated [3H]dopamine release | 10.1016/s0014-2999(01)01071-8_Science Hub

www.tesble.com

I found this earlier work on that trishomocubane in which their initial position was that the class just modulates amphetamine-mediated dopamine release. BUT at that time Compound 12 had not been identified.

But look carefully and you will notice something familiar... it is a super-structure of fencamfamine. NOT camfentamine - like fencamfamine the researchers settled on an N-ethyl moiety. I check and it does indeed overlay one of the four stereoisomers of fencamfamine - a class I had mentioned but not really considered.

 

[Phobos]

Dopamine is metabolised into Norepinephrine/Noradrenaline and then into Epinephrine/Adrenaline, does dopamine release accelerate the rate at which this metabolization happen?
If yes would this make only increasing dopamine levels impossible?

 

[4DQSAR]

Dopamine is metabolised into Norepinephrine/Noradrenaline and then into Epinephrine/Adrenaline, does dopamine release accelerate the rate at which this metabolization happen?
If yes would this make only increasing dopamine levels impossible?

What happens downsteam is unrelated to the title of the thread.

I very carefully framed the limited cases and strength of the evidence AND provided that evidence.

 

[4DQSAR]

Sci-Hub. Comparative biochemical and behavioural effects of fencamfamine and dl-amphetamine in rats / Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1983

BTW as I always seek to provide a basis for a hypothesis, this 1983 paper suggests that fencamfamine to be an indirect dopinergenic agonist of the non-amphetamine type. So while old and while only a hypothesis itself, it is in the conclusion so even in the 80s, people were already noting that although fencemfamine overlays amphetamine, it's action may differ.

Note that FCF produced increases in both DOPAC and homovanillic acid while (DL) amphetamine reduced DOPAC but increased homovanillic acid (but less than FCF) at an equipotent dose. This suggests a different mechanism. That FCA is a releaser, not a reuptake inhibitor.

Is it selective? Well yes, but a FCF may not be totally selective. But we can go back and look at the paper from which I divined the FCF was selective handily offers a single, simple modification that DOES make it extremely selective i.e. NET >20000 and SERT >20000 while DAT is 101±5. THAT is selective.