Selective Dopamine Releasing Agents ?

[4DQSAR]

See you almost get it yet you dont. You think more dopamine selective = more euphoric.

No - I don't like ANY stimulants as I posted earlier. So of course 'I don't get it', but this thread is devoted to selective dopamine transport ligands. Not to any one person's subjective response.

My position is purely data led. I have located and provided the data. LOTS of data. LOTS and LOTs and LOTs of data.

I KNOW how much ethylphenidate we sold and I provided a HEAP of references to back up my position. Confirmation bias is natural and human, but be aware of it and account for it.

You said it was fine to disagree as YMMV... so why argue? If you prefer less selective ligands, fine. We are all entitled to hold an opinion. But it IS an opinion.

If you have a human study, I would love to read it as there more data is always a good thing. in vitro studies are shaky at best and even rodent models can perform very poorly. There is a term used by those who employ rodent models - ratatonia.

The reason being that a whole range of ligands from stimulants to opioids to anxiolytics to I do know what; but for whatever reasons, rodents just become catatonic so how does one test the subjective activity of a high dose of a stimulant using rodents if all they do is to freeze?

 

[4DQSAR]

Oh, I also forgot modafinil.

'R-Modafinil(Armodafinil):A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse'

DOI:10.1016/j.biopsych.2012.03.022

This employed both knockout mice and displacement of WIN35428 to model activity. The ligand is listed in a paper I linked to in an earlier post.

Again, note that it's one of the two stereoisomers that demonstrates the selectivity. As mentioned, the R/S identification is based on the CIP rules.

I believe I have now provided references to each class of agent I am aware of apart from those @Smyth2 pointed out first.

I suspect that the pharmokintetics plays a large part in why modafinil (or indeed any stimulant) isn't abusable. Just as homomazindol has a slow onset and long duration of activity, so does Armodafinil.

After all, this thread is about dopamine so I have sought to at least locate only ligands selective to DAT.

Any subjective effects are subject to YMMV. But we are not discussing subjective effects...

 

[TheLightBringer]

Oh, I also forgot modafinil.

'R-Modafinil(Armodafinil):A Unique Dopamine Uptake Inhibitor and Potential Medication forPsychostimulant Abuse'

DOI:10.1016/j.biopsych.2012.03.022

I believe I have now provided references to each class of agent. I suspect that the pharmokintetics plays a large part in why modafinil isn't abusable. Just as homomazindol has a slow onset and long duration of activity, so does Armodafinil.

This is exactly what I mentioned earlier, I mentioned modafinil because its not euphoric at all. You proved my point, selective DRIs are not euphoric. And I read that you didnt like stimulants but did not choose to use it as an argument as its somewhat of a strawman. Unlike you who claim its due to my personal preference. Its literally proven through studies through tons of species which we obviously cant do on humans as it would be inhumane, besides that the only way its proven in humans is by thousands of anecdotes.

Even the GBR and WIN series of drugs, some of which were truly selective for dopamine and higher DAT affinity than traditional stims failed to have any reinforcing effects.

Even when others told you in the thread that D-MPH and EPH are not selective DRIs you .
refuse to see it lol. The reason I keep arguing as you said is because there is too much misinformation about how pure dopaminergics will be more euphoric than balanced DA/NE stims.

I dont see how the data you provided is relevant to pure DAT selective drugs being more euphoric, because ive tried looking for studies all over google and asked AI and cant find a study that mentions a pure DRI will provide more euphoria. Neither can I provide a study that says explicitly that the proper NET to DAT balance causes more euphoria because no one would bother to conduct a study that caters to the preference of drug abusers. As far as providing data the backing of my arguments would be limited:

There and back again: a tale of norepinephrine and drug addiction - PubMed

Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could...

pubmed.ncbi.nlm.nih.gov

Norepinephrine and Stimulant Addiction - PMC

No pharmacotherapies are approved for stimulant use disorders, which are an important public health problem. Stimulants increase synaptic levels of the monoamines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Stimulant reward is ...

pmc.ncbi.nlm.nih.gov

Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin - PubMed

A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates, in animal models, the reinforcing effects of central nervous system stimulants such as cocaine and amphetamine. The role DA plays in mediating amphetamine-type subjective effects of stimulants in humans...

pubmed.ncbi.nlm.nih.gov

Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior - PubMed

Male rats were given 6-hydroxydopamine-induced lesions of the locus coeruleus (LC) or the dorsal noradrenergic bundle (DNAB), prior to the measurement of locomotor and rearing activity induced by D-amphetamine. The increased locomotor activity induced by D-amphetamine (1.8 mg/kg) was...

pubmed.ncbi.nlm.nih.gov

https://www.sciencedirect.com/science/article/abs/pii/0024320563900870?via%3Dihub

What changed my mind was the discussion on DrugNerds 8 years ago, I managed to find the old post but the studies linked were deleted and I have no recollection of their names since it was back in 2018

Might be able to find it using internet archive.

Not trying to come off as an asshole, you are usually one of the posters on this forum with high quality posts.

 

[TheLightBringer]

Also not fully related to stimulants but partly to my suggestion that NE plays a key role in euphoria:

Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens - PubMed

Increasing evidence suggests that in addition to the mesoaccumbens dopamine (DA) system other neurotransmitter and brain systems are also involved in opiate addiction. Recent evidence points to a major involvement of brain norepinephrine (NE) in the behavioral and central effects of opiates and...

pubmed.ncbi.nlm.nih.gov

Even in Morphine NE is needed for the rewarding effects

 

[4DQSAR]

Also not fully related to stimulants but partly to my suggestion that NE plays a key role in euphoria:

Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens - PubMed

Increasing evidence suggests that in addition to the mesoaccumbens dopamine (DA) system other neurotransmitter and brain systems are also involved in opiate addiction. Recent evidence points to a major involvement of brain norepinephrine (NE) in the behavioral and central effects of opiates and...

pubmed.ncbi.nlm.nih.gov

Even in Morphine NE is needed for the rewarding effects

In BEHAVIORAL effects - here, we are looking at the objective action of a ligand, not it's subjective effects. I even pointed this out and yet once again it's back to arguing over what is and isn't 'euphoric'. Can you point to a single post where I asserted that a ligand was or was not euphoric?

With all such things, YMMV.

I'm reponding to the OP and the name of the thread.

 

[fuckabout89]

Unfortunately there doesnt seem to be any DRAs purely selective for dopamine. Wikipedia lists cis-4-MAR as one of the most dopamine selective stimulants but that still releases NET.

2-FluoroMethCathinone and 3-Methoxy-Methcathinone are also listed as more selective for dopamine compared to most other stims but due to the similarity of DAT and NET transporters its unlikely to get that to work

There are some selective DRIs though like amfonelic acid or some of the RTI analogues but as far as releasing agents go it doesnt seem to exist as of now. I wonder if some of the SDRA tryptamines could be modified to be more selective for dopamine and less for

The thing is pure DRIs suck for recreational purposes, try it yourself, the -afinils, amfonelic acid, pemoline. No real fun to be had. Norepinephrine plays a key role in arousal and euphoria from stimulants

serotonin though. Might be the best bet outside of finding a completely new scaffold

Yup its a lot more complicated than purely dopamine its more about the ratio of the other neurotransmitters.

 

[4DQSAR]

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

I found this. I know nothing about the class but it's structure is odd, that's for sure. Some sources state that it is a selective releaser, other do not. But the weight of evidence did suggest it is. Is it FUN? No idea. BUT it IS a selective releaser based on the weight of evidence. So success at last?

A meta fluoro benzylamine with a truly BIZARRE but bulky N-methyl group. PubChem falls over trying to match the structure.

Compond 12 is the specific example I am looking at.

Sci-Hub: are you are robot?

Again, another extremely niche compound. I freely admit that I cannot find a more recent paper. I THINK it's used in research, but again, @Smyth2 certainly flagged the class if not the specific ligand.

As @fuckabout89 rightly points out, the whole idea of what is and what is not euphoric is slippery. Until selective NMDA antagonists were discovered, it was sort of assumed that ultimately dopmaine had to be part of any euphoria. Yet in primate models, self-administration of (S) ketamine (Esketamine™) was observed. Now here we have to ask if those primates were kept in a comfortable, safe, secure enclosure because we know that drugs that have no street value are still abused within prisons. I assume because ANY ASC is considered a good thing.

I mean, bupropion (Wellbutrin™)? Or quietipine (Seroquel™)? Or even hyoscine butylbromide (Buscopan™) - because when smoked, the quaternary ammonium salt is reduced so the pyrolysis product crosses the BBB. But I mean, smoking an IBS medication to get a hyocine trip? So with those primate studies, was it euphoria or was it just an ASC? Similarly I know of people who injected cyclizine compulsively because it produces a very brief rush. But that's a medication for the treatment of travel sickness.

In Russia, they even went one better. The drug nicknamed 'four monther' (tropicamide) is abused because it's a potent anticholinergic (like hyocine AKA Buscopan™) just more dangerous, as the nickname hints at.

 

[TheLightBringer]

https://doi.org/10.1016/j.bmcl.2010.11.075

I found this. I know nothing about the class but it's structure is odd, that's for sure. Some sources state that it is a selective releaser, other do not. But the weight of evidence did suggest it was.

Compond 12 is the specific example I am looking at.

Sci-Hub: are you are robot?

Again, another extremely niche compound. I freely admit that I cannot find a more recent paper. I THINK it's used in research, but again, @Smyth2 certainly flagged the class if not the specific ligand.

As @fuckabout89 rightly points out, the whole idea of what is and what is not euphoric is slippery. Until selective NMDA antagonists were discovered, it was sort of assumed that ultimately dopmaine had to be part of any euphoria. Yet in primate models, self-administration of (S) ketamine (Esketamine™) was observed. Now here we have to ask if those primates were kept in a comfortable, safe, secure enclosure because we know that drugs that have no street value are still abused within prisons. I assume because ANY ASC is considered a good thing.

I mean, bupropion (Wellbutrin™)? Or quietipine (Seroquel™)? Or even hyoscine butylbromide (Buscopan™) - because when smoked, the quaternary ammonium salt is reduced so the pyrolysis product crosses the BBB. But I mean, smoking an IBS medication to get a hyocine trip? So with those primate studies, was it euphoria or was it just an ASC? Similarly I know of people who injected cyclizine compulsively because it produces a very brief rush. But that's a medication for the treatment of travel sickness.

In Russia, they even went one better. The drug nicknamed 'four monther' (tropicamide) is abused because it's a potent anticholinergic (like hyocine AKA Buscopan™) just more dangerous, as the nickname hints at.

Reminds me of that old krokodil addict interview where the guy injects tropicamide seemingly around his groin area and collapses down a flight of stairs, smashing his head through a window

 

[4DQSAR]

Reminds me of that old krokodil addict interview where the guy injects tropicamide seemingly around his groin area and collapses down a flight of stairs, smashing his head through a window

Well, humans are odd. We don't really know if animals think about the future or understand death in the same way as we do. So even the epicurians only listed freedom from PHYSICAL pain as a requirement for happiness.

Russia is grim. Kids are pessimistic, depressed and importantly, feel they have so few freedoms that if someone in power decides you should die, you die. So for them, thinking more than a few hours into the future simply doesn't occur to them.

I missed that specific case but I worked with a team in Portugal to identify exactly what it was in Krokodil that caused flesh to rot and bones to weaken. It turned out that the RP/I formed phosphine and breathing that in will destory the inner structure of bones. The rotting flesh was a mixture of them shooting an unrefined mixture of compounds, some of which were phosphonamides (a PH2- replaced the -CH3 of the amine.

Both were due to RP/I being used in the synthesis. We really did wonder if a HR booklet would be a good thing (showing people how to make & consume desomorphine in a safer way) ot a bad thing (more people might choose to experiment with Krokodil if they thought it was safe).

In the end Putin solved the problem by banning all codeine and dihydrocodine containing [P] medications. All are now [POMs] So we dodged a bullet because if we did or if we didn't produce that booklet, we would have been blamed for deaths).

I think Michael still has a copy but I couldn't swear to it.

But tropicamide is the DMT to hyocines LSD. Much faster onset, much more powerful, tends to mess people up a lot sooner...

 

[TheLightBringer]

Well, humans are odd. We don't really know if animals think about the future or understand death in the same way as we do. So even the epicurians only listed freedom from PHYSICAL pain as a requirement for happiness.

Russia is grim. Kids are pessimistic, depressed and importantly, feel they have so few freedoms that if someone in power decides you should die, you die. So for them, thinking more than a few hours into the future simply doesn't occur to them.

I missed that specific case but I worked with a team in Portugal to identify exactly what it was in Krokodil that caused flesh to rot and bones to weaken. It turned out that the RP/I formed phosphine and breathing that in will destory the inner structure of bones. The rotting flesh was a mixture of them shooting an unrefined mixture of compounds, some of which were phosphonamides (a PH2- replaced the -CH3 of the amine.

Both were due to RP/I being used in the synthesis. We really did wonder if a HR booklet would be a good thing (showing people how to make & consume desomorphine in a safer way) ot a bad thing (more people might choose to experiment with Krokodil if they thought it was safe).

In the end Putin solved the problem by banning all codeine and dihydrocodine containing [P] medications. All are now [POMs] So we dodged a bullet because if we did or if we didn't produce that booklet, we would have been blamed for deaths).

I think Michael still has a copy but I couldn't swear to it.

But tropicamide is the DMT to hyocines LSD. Much faster onset, much more powerful, tends to mess people up a lot sooner...

Truly awful situation, all those videos of the guys cooking that sludge up without even attempting to clean out the RP or Iodine then going right for a vein after. Ive always wanted to spend a full 24 hours in their body and mind to see what its like, the desperation of knowing youre rotting from the inside out but the hopelessness and desire for the drug simply too strong and overpowers your sense of self-preservation completely.

 

[N0ph0n0]

Well, humans are odd. We don't really know if animals think about the future or understand death in the same way as we do. So even the epicurians only listed freedom from PHYSICAL pain as a requirement for happiness.

Russia is grim. Kids are pessimistic, depressed and importantly, feel they have so few freedoms that if someone in power decides you should die, you die. So for them, thinking more than a few hours into the future simply doesn't occur to them.

I missed that specific case but I worked with a team in Portugal to identify exactly what it was in Krokodil that caused flesh to rot and bones to weaken. It turned out that the RP/I formed phosphine and breathing that in will destory the inner structure of bones. The rotting flesh was a mixture of them shooting an unrefined mixture of compounds, some of which were phosphonamides (a PH2- replaced the -CH3 of the amine.

Both were due to RP/I being used in the synthesis. We really did wonder if a HR booklet would be a good thing (showing people how to make & consume desomorphine in a safer way) ot a bad thing (more people might choose to experiment with Krokodil if they thought it was safe).

In the end Putin solved the problem by banning all codeine and dihydrocodine containing [P] medications. All are now [POMs] So we dodged a bullet because if we did or if we didn't produce that booklet, we would have been blamed for deaths).

I think Michael still has a copy but I couldn't swear to it.

But tropicamide is the DMT to hyocines LSD. Much faster onset, much more powerful, tends to mess people up a lot sooner...

Wow, that sounds grim but also very interesting.

 

[saadman]

Methamphetine. It’ll flood you and inhibit reuptake…. Im just kidding btw, i mean it does do that but it’s a sarcastic suggestion. Dont do
It.

 

[4DQSAR]

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.

Dopamine uptake inhibiting versus dopamine releasing properties of fencamfamine: An in vitro study | 10.1016/0006-2952(83)90181-8_Science Hub

www.tesble.com

Now remember that there are four stereoisomers and that the first paper only overlays one. Anyone care to guess which one? The (1S,2S,4R) and as I had previously mentioned, so far nobody has been able to resolve the four stereoisomers BUT at the very least, the trans-pair can likely be resolved using the differing physical properties. But then, a chiral acid would likely be needed and let's face it, it's an old medicine that nobody can therefore patent so is not a scaffold likely to see any new research.

BUT it there were more selective releasers, at the very least, a training-set may be possible.

 

[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.

It is only weak evidence but the conclusion was made using raecemic fencamfamine. I suggested only one stereoisomer MAY be selective to DAT.

Note that FCA produced increases in both DOPAC and homovanillic acid whie (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.

 

[4DQSAR]

OK - 18F meta fluoro fencamfamine is a known radioligand.

I would be cautious and see if the meta methyl homologue is similarly selective because it's a sacrificial moiety i.e. the body will oxidize that labile methyl so metabolism is far more uniform. But obviously it isn't a radioligand.

 

[Smyth2]

4DQSAR i was looking at the synthesis of the compound (you are right in identifying the N-(meta-fluorobenzyl)-N-methyl-amine as the most potent compound in the class.

Although I know it is not allowed to experimentally discuss the synthesis I can still discuss some of the theoretical chemistry with you.

The starting material is the same no matter what the final route taken is:

Cookson's dione (aka Cookson’s diketone) [2958-72-7]
https://orgspectroscopyint.blogspot.com/2016/10/cooksons-dione.html
Ito, Felicia; Petroni, Jacqueline; De Lima, Dênis; Beatriz, Adilson; Marques, Maria; De Moraes, Manoel; Costa-Lotufo, Letícia; Montenegro, Raquel; Ferreira Magalhãe, Hemerson; Do Ó Pessoa, Cláudia . (2007). Synthesis and Biological Evaluation of Rigid Polycyclic Derivatives of the Diels-Alder Adduct Tricyclo[6.2.1.02,7]undeca-4,9-dien-3,6-dione. Molecules, 12(2), 271–282. doi:10.3390/12020271

I'm still working on the file i have for this exact compound and have not finished it yet as of this date.

 

[4DQSAR]

Well, you noted where I spotted that insane trishomocubane and it doesn't take a genius to work out that it's just space-filling a hydrophilic pocket. Now why that one, I don't know. But I don't think it's a secret that steric bulk is tolerated. One person I know obtained nomifensine before the Alfa Aecer merger (i.e. when they weren't particularly looking at who bought simply because the prices charge made using them as a source impractical). At high doses they did reach for the C word when trying to describe the subjective effects.

Now we know that dichlorfensine was studied because it became known that nomifensine had abuse potential and if nothing else, it does show that the (problematic) aryl amine isn't a requirement. It would be interesting to test the minimum-energy conformation of the (S) overlays other classes.

The fact that they initially offered the racemate MAY suggest that the two have different activities.

I think what made meta substituted derivatives of fencamfamine interesting is the simplicy of the synthesis. As I noted, you end up with 90% trans but it would be really nice to find a way of resolving that trans pair.

 

[4DQSAR]

OK - the reason a trishomocubane was chosen was simply that while dodecahedrine has been synthesized (being a Buckminster fullerene), it's currently impossible to produce the entire 'ball' AND add two substituents on the same edge. So what researchers noted was that some bonds could be omitted while still providing that EXTREMELY specific bond-angle between the two (108º) which is, I suggest, an example of in-silico modelling suggesting that the relative spatial position and orientation of the aromatic and basic nitrogen and it's lone-pair may be 'tuned'.

But I think it worth noting that because of the bridge, the bond-angles in the case of the trans norboranane moiety found in fencamfamine it's 103º and 108º and that is a reasonable 'rate of exchange' when you compare the synthetic complexity. Certainly a LOT closer than the 120º in simple PEAs. I believe that it's shown to be 'close enough'. Worth noting that GI Poos is listed in the original 1961 paper (McNeil) which itself references the 1940s work on N-ethyl-2-phenylcyclopentan-1-amine. Increased steric bulk appears confir selectivity and I can only guess that the work was also demonstate how much bulk could be tolerated.

It isn't a new idea, merely we now have the synthetic techniques to produce these ligands using 'exquisite tecnology'. If you read the history of MK-801 it was quickly regonized that there existed a 'perfect' spatial relationship between the A-aromatic and the amine. In that case it turned out that the 'magic angle' was 107.5º. Useful to know but nobody went on to really make use of the knowledge given the synthetic complexity.