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DA transporter inhibitor & Mu Agonist?

LikeADaVinci

LikeADaVinci

Bluelighter
Joined
Dec 31, 2023
Messages
28
Hello bluelighters,

So, I’m curious as to Mu receptor agonists (pain-killing opioids) with strong dopaminergic activity, for the sake of developing an analgesic which blocks dopamine reuptake thereby stimulating the CNS and combating deadly respiratory depression inherit to opioids.

It also seems like the recreational potential of such a compound would be increased, since, you have the mu agonist activity, which inhibits GABA inter neurons in the ventral tagmental area thereby disinhibiting dopamine release in the accumbens, while simultaneously blocking the reuptake of dopamine in the accumbens.

Take this compound for instance, and it’s activity profile:

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IMG 2441 — Postimages

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What do you think of such a combination of activities / receptor targets?

LikeADaVinci
 
Well there are already drugs like pethidine and the various pethidine analogs, but these aren't really any safer than other opioids due to their dirty effects. And there are milder examples like lefetamine. But you aren't going to find many examples of opioids that act potently at both the MOR and the DAT simultaneously, and without also being promiscuous for sites (like the NET or SERT, or NMDAR) which make these opioids rather dirty and therefore a danger with respect to drug interactions/unpredictable effects.
 
What I’m doing is looking at known targets for the mu receptor specifically, and going through them one by one (there are thousands) to find the ones which have the highest activity as well for the DAT (dopamine active transporter) while sparing NE, 5-HT, choline or cholinesterase, NMDA, and kappa opioid targets.

That way, it’s not “dirty” as you say, but preferential for DAT & Mu specifically - if that compound were found, I think it might be a breakthrough in pain management while sparing so many deaths from respiratory depression.

I’m also looking for the simplest possible compound, structurally (as few stereocenters as possible while having as few ring structures and Moities as possible) so that the synth is easy.

LikeADaVinci 👍
 
Demerol - dopaminergic opioid (DAT/NET + Mu Opioid agonist)
Tramadol - Mu Opioid + SERT/NET

Methylphenidate (Ritalin) + Oxycodone (Oxy-IR) were the only drugs in my entire life to give me true overpowering euphoric pleasure. Wish I could’ve taken them together 20 years ago when naive to every substance

Brompton Cocktail or an I.V. Speedball …..just pure heaven
 
Well here specifically is the link for the target compound I’m looking at: you can modify the structure and run the receptor target simulator to see how analogues differ in DAT / Mu targeting: http://www.swisstargetprediction.ch/result.php?job=1819847343&organism=Homo_sapiens

Here is a list of analogues with dopaminergic affinity as receptor blockers: http://www.swisstargetprediction.ch/molecules.php?job=1819847343&target=7&method=3D

And here is a list of analogues with potent mu receptor targeting: http://www.swisstargetprediction.ch/molecules.php?job=1819847343&target=0&method=3D

Perhaps you bluelighters can help me find a compound (or analog / homolog) using this tool, with specific DAT blocking activity and mu agonist activity while sparing the adrenic, serotonergic, kappa, NMDA, and 5-ht / DA receptor agonist activities?
 
I also want to mention with this one:



It ALSO seems to INHIBIT VMAT2 (vesicular monoamine transporter) https://en.m.wikipedia.org/wiki/Vesicular_monoamine_transporter, much like AMPHETAMINE does, and this compound only interacts with dopaminergic targets and opioid targets, so

So it’s a dopaminergic RELEASING AGENT, reuptake inhibitor, and mu-opioid agonist:

The Dopaminergic efflux in the nucleus accumbens shell must be OFF THE CHARTS (very high over baseline), so this will definitely inhibit respiratory depression & prevent deaths in overdose, not to mention feel ABSOLUTELY MARVELOUSLY EUPHORIC
 
^^^^keep in mind that that tool is purely predictive and activity in humans/animals could be quite different given the variables involved.

But I still can't picture a highly specific MOR agonist that also possesses highly specific affinity for the DAT without flipping a whole host of other unwanted switches in the process. I'm no SAR/QSAR expert, but from what I recall, MOR agonists and DAT inhibitors typically have rather different optimal stereochemical configurations and molecular sizes that are best suited for their target sites, so I'm not so sure you'll come across something specific for both within the same molecule. Perhaps some wacky fenethylline-like prodrug could be made that breaks down into two separate molecules (an opioid and a DRI), but a speedball in prodrug form sounds like risky business.
 
Nucleus accumbens dopamine release doesn't impinge on breathing. If there is too much inhibitory at the medulla respiratory depression will occur, hence why opioids cause respiratory depression despite disinhibiting dopamine release in the NA.
 
By the way, is there any known website / database / program that you know of which delivers up a synthesis for a final finished molecule you input?
 
LikeADaVinci said:
What I’m doing is looking at known targets for the mu receptor specifically, and going through them one by one (there are thousands) to find the ones which have the highest activity as well for the DAT (dopamine active transporter) while sparing NE, 5-HT, choline or cholinesterase, NMDA, and kappa opioid targets.

That way, it’s not “dirty” as you say, but preferential for DAT & Mu specifically - if that compound were found, I think it might be a breakthrough in pain management while sparing so many deaths from respiratory depression.

I’m also looking for the simplest possible compound, structurally (as few stereocenters as possible while having as few ring structures and Moities as possible) so that the synth is easy.

LikeADaVinci 👍
Click to expand...


I think if your compound was ever created, it wouldn’t solve the problem of respiratory depression is dopamine is not really involved in that. maybe very strong norepinephrine reuptake might help a bit in regards to combating respiratory depression or unconsciousness. A MU agonist with strong dopamine reuptake. inhibition would act more like the infamous speedball (mixture of cocaine and heroin) which has greater addictive potential than either drug alone, and actually increases the risk of respiratory depression and overdose. nevertheless, from a purely recreational perspective, you could just take an opioid along with a psychostimulant like methylphenidate or amphetamine. that would be much easier and more efficient than developing a structurally complex compound which acts on two separate targets.
Actually, some doctors do prescribe methylphenidate along with opioid therapy, especially in palliative care. The methylphenidate combats opioid induced drowsiness, cognitive/memory impairment and may possibly improve analgesic potency. overall, it definitely improves the quality of life of patience, but I would definitely take caution of the extreme addictive potential of combining opioids with psychostimulants.
 
Don't confuse affinity with efficacy.

Don't presume that the therapeutic window of one activity is the same or even overlaps the therapeutic window of another activity.

I believe it's norpethidine (which has a longer half-life than it's parent) that has substantial DRI activity.

That's why people may be prescribed pethidine in hospital and dopaminergic side-effects only become apparent after chronic administration. There are many papers on norpethidine toxicity with seizures and other potentially fatal effects.

The current research into analgesics is to target the NOP receptor. Previously, joint MOP/DOP ligands were demonstrated to produce far less respiratory depression. An Austrian researcher called Helmut Schmidhammer spent over a decade researching 14-alkoxymetopon derivatives (joint MOP/DOP) but after about 2000, focus was more on less abusable (NOP ligands) and those which do not produce dependence (e.g. Olinceridine).

Forgive me, but wouldn't it be much easier to produce a codrug that is metabolized into an opioid and a DRI? Much simpler.
 
“Forgive me, but wouldn't it be much easier to produce a codrug that is metabolized into an opioid and a DRI? Much simpler.”

Sure, it would be much simpler, but the best things in life usually aren’t the easiest … I’m trying to for the first time specifically model a single molecule which is both dopaminergic and analgesic — if not to alleviate the deadly respiratory depression, then to increase the quality of life of patients nodding out taking high doses of oxy / fentanyl for cancer pain, for instance …

Why the resistance to finding a single compound that does both?
 
Also the neurotoxicity and undesirable side effects of pethidine are not SPECIFICALLY due to its dopaminergic stimulatory effects but due to its dopaminergic Neurotoxic effects
 
Because their is absolutely no certainty that such a compound exists. Matching MOR and DRI at exactly the same doses... unlikely.

Medicinal chemistry is about practical problem solving.

I've pointed to other approaches that have been researched and proven to work. WHY specifically seek DRI/MOR activity?

Why reinvent the wheel?

Things like nortilidine are noted as DRIs but they still produce respiratory depression suggesting that it isn't as simple as DRI activity offsetting the side-effect.
 
LikeADaVinci said:
Why the resistance to finding a single compound that does both?
Click to expand...

Because its difficult to near impossible to find a single key that fits 2 very different locks, and that also doesn't happen to open any other locks. It is not a big deal when the targets are similar (like the DAT versus the NET), but when targets are very different, it becomes a major problem.

I mean just consider the massive difference in the endogenous keys (ligands) for the DAT versus the MOR. The endogenous ligand for the DAT is a very simple monoamine, whereas the endogenous ligands for the MOR are complex peptides. These keys are shaped very differently, so much so, that these differences preclude a single compound from being able to selectively bind at just those two sites, and nothing else.
 
“that these differences preclude a single compound from being able to selectively bind at just those two sites, and nothing else.”

Oh really? Well then look at this!

 
LikeADaVinci said:
“that these differences preclude a single compound from being able to selectively bind at just those two sites, and nothing else.”

Oh really? Well then look at this!

Click to expand...

You do know the difference between dopamine receptor ligands and dopamine transport ligands, right?

Also, as stated, affinity ≠ efficacy.

Learn the QSAR of opioids and you will discover the above is an ANTAGONIST which is quite likely to act as a neuroleptic.

What indications would you suggest your imaginary drug be prescribed for?
 
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