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  • N&PD Moderators: Skorpio

Psychedelic Opiates ?

Depending on the study you read, ibogaine is sometimes cited as an opioid with significant psychedelic (5HT2A agonism) effects.

Thinking about it from a receptor focused perspective, it is going to be a challenge to develop a ligand at monoamine and opioid receptors. The monoamine receptors bind smaller ligands (serotonin, dopamine, noradrenaline) where the opioid receptors bind short peptides (endorphin, enkephalins, dynorphin). These will predispose the receptors to ligands both of different sizes, but more crucially different patterns of H-bond donors and hydrophobic bits.

Focusing back on ibogaine, one thing to notice is that it isn’t particularly potent at any site. It’s binding affinities for sigma2, kappa and mu opioid, and serotonin receptors is in the micromolar range (rather than the nanomolar range like fentanyl or lsd). This is likely a manifestation of the compromises required to make a drug active at these disparate receptor systems.
 
Skorpio said:
Depending on the study you read, ibogaine is sometimes cited as an opioid with significant psychedelic (5HT2A agonism) effects.

Thinking about it from a receptor focused perspective, it is going to be a challenge to develop a ligand at monoamine and opioid receptors. The monoamine receptors bind smaller ligands (serotonin, dopamine, noradrenaline) where the opioid receptors bind short peptides (endorphin, enkephalins, dynorphin). These will predispose the receptors to ligands both of different sizes, but more crucially different patterns of H-bond donors and hydrophobic bits.

Focusing back on ibogaine, one thing to notice is that it isn’t particularly potent at any site. It’s binding affinities for sigma2, kappa and mu opioid, and serotonin receptors is in the micromolar range (rather than the nanomolar range like fentanyl or lsd). This is likely a manifestation of the compromises required to make a drug active at these disparate receptor systems.
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Akuammine and Ibogaine derivatives would come the closest but Ibogaine has such insignificant 5HT2A and Mu Opioid agonism. Its more like a disso with serotonergic activity and K-opioid activity.
 
Skorpio said:
...micromolar range (rather than the nanomolar range like fentanyl or lsd). This is likely a manifestation of the compromises required to make a drug active at these disparate receptor systems.
Click to expand...

I'm ashamed to say that I mis-read a paper on a novel class of opioid. I kept thinking 'these numbers seems impressively small' until I noted the very small type that said 'micromoles' and not 'nanomoles'.

But it demonstrates serendipity because the paper only covered examples with secondary amines e.g. the N-methyl or N-n-butyl examples but there were enough known ligands to assert that the chiral N,N-dimethyl example may be far more potent. So we had it made and it was indeed far more active.

Not super-active. I mean about an order of magnitude more potent than morphine. Some would consider that to be potent but it used an optical resolution and was elsewhere costly and tricky to synthesize. But we wouldn't know what we DO know if I hadn't made the mistake...
 
TheLightBringer said:
Akuammine and Ibogaine derivatives would come the closest but Ibogaine has such insignificant 5HT2A and Mu Opioid agonism. Its more like a disso with serotonergic activity and K-opioid activity.
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Good to know. Wiki numbers were all over the place and I was being too lazy to dig for a paper that screened all of the binding affinities in the same panel (best practice imo).
 
It makes me wonder... How many ibogaine analogues you could come up with that have both a high serotonin and opioid agonism to them ?
 
This database compiled a number of studies and it looks like ibogaine does not bind directly to monoamine receptors across a few screens.

It does look like in one screen (Ray TS 2010) ibogaine was found to be about half as strong a mu ligand as a kappa ligand. This screen found no activity at monoamine receptors. It seemed to be most potent at sigma 2 (~10 fold more than KOR) and slightly less potent at sigma 1 than MOR. NMDA binding is on the same order of magnitude to KOR binding.
 
MedicinalUser247 said:
It makes me wonder... How many ibogaine analogues you could come up with that have both a high serotonin and opioid agonism to them ?
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You have to remember that there are many classes of opate receptor and manifold classes of serotonin receptor.

We had to ditch what until that point had looked like a really good legal alternative to MDMA until we discovered that it had significant 5HT2b affinity. In spite of our thinking that unlike say a diet medication people would not be using the candidate on a regular basis, one always has to assume that a minority MAY.

It's not a secret that it was based on a known class but as mentioned elsewhere, if you are unable to carry out very large stage 3 trials, one has to take the line that if a risk is known, the candidate MUST be dropped.
 
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What I'm looking for, to be more specific, is a Drug that would target both the 5-HT2a and Mu-opioid receptors.
 
MedicinalUser247 said:
What I'm looking for, to be more specific, is a Drug that would target both the 5-HT2a and Mu-opioid receptors.
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Ibogalogs would likely be your closest bet, unfortunately a derivative of ibogaine that is curriently efficient enough as an agonist at both receptor sites does not exist and the structure likely doesnt allow for it effectively. The indole is sort of ”trapped” within the structure and the structure of Iboga if modified to be more effective for the mu-Opioid receptor would be even less likely to activate 5HT2A.

Viceversa the ibogalogs that have higher 5HT2A agonism essentially lose more of what little mu-Opioid agonism they had in the first place
 
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"20/20 vision blurred and can't even feel the syrup, I'm on Acid!" - lil whyte

I suspect that when you hit the sweet spot with any psychedelic, that the euphoria of the psychedelic in of itself - is potent enough to outweigh any opiate feelers IMO.

I only speculate this to be the case, because railing oxy never really did much to anything besides maybe bringing a sense of control behind the wheel, during mushroom or LSD peaks..now the next morning or in the afterglow, yes..but still feels a bit suppressed. Kind of like when you take a stimulant like addy and it outweighs the opioid/opiate buzz or some would even say it spoils it.

Also, yeah I think dxm is kinda cool in regards to opiate like feeling-while tripping(although dissociative). I forget EVERYTHING but I think its considered a pro drug and I mean the first plateaus are probably best at feeling this energetic angelesic
 
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SWEET_CAROLINE
N-dodecyl-2-amino-1-(3,4-methylenedioxyphenyl)-propane

Sassy!
 
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