Opioid potency/molecular complexity, inversely proportional to euphoric potential.

[sarbanes]

My 1st post! I’m working on a theory based on personal, anecdotal evidence, and others’ reports. The theory is, as an independent factor, generally, the simpler the structure of the opioid, the more euphoric potential of that molecule in humans. And part two is, the more potent the opioid analgesic, the lower the euphoria produced at effective (analgesic) doses. In otherworlds, something like carfentanil I hear produces relatively little euphoria (as compared to fentanyl, for one), and if you equalize its therapeutic index ratio, it is consistent with the theory. So, by this theory, a simple molecule with lower than average potency would have greatest potential for causing the most profound euphoria. Good candidates would be lower potency homologues (simple alkyl) of the benzimidazole type, tramadol, and ketobemidone (and lower potency analogs), and several in the methadone series (perhaps Dipipanone). I have noticed these correlation time and again. Anyone care to comment. Tnx
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Now, B4 I get the inevitable flame like "then how come codeine doesn't produce as much euphoria, huh", or "your wrong man, fentanyl really gets me high", remember, I am postulating this as only one *independent* factor. It in no way is meant to account to, or control for every mechanism involved. Sorry to preempt, but I just know that I would get a flame.

 

[Smyth]

The theory is, as an independent factor, generally, the simpler the structure of the opioid, the more euphoric potential of that molecule in humans. And part two is, the more potent the opioid analgesic, the lower the euphoria produced at effective (analgesic) doses.

So codeine > morphine > H at producing euphoria then? I dont think so
But now I see you are referring to purely opioid compounds not natural goodies. I thought the reason carfentanil doesnt produce much euphoria is because users tend to hit the canvas before they know what hit them. I think its much more complex though than just looking for a simple relationship based on potency, speed of onset or duration. Although all of these factors may play a role the picture has other factors too and some of these are not going to be obvious or predictable. Study the pharmacology of individual isomers of OMF on pubmed. Psychological and physical addiction is highly dependent on sterechemistry. I'd like to read other peoples answers though since understanding the term "euphoria" requires first-hand experience and not just reading other peoples accounts.

 

[sarbanes]

So codeine > morphine > H at producing euphoria then? I dont think so
But now I see you are referring to purely opioid compounds not natural goodies. I thought the reason carfentanil doesnt produce much euphoria is because users tend to hit the canvas before they know what hit them. I think its much more complex though than just looking for a simple relationship based on potency, speed of onset or duration. Although all of these factors may play a role the picture has other factors too and some of these are not going to be obvious or predictable. Study the pharmacology of individual isomers of OMF on pubmed. Psychological and physical addiction is highly dependent on sterechemistry. I'd like to read other peoples answers though since understanding the term "euphoria" requires first-hand experience and not just reading other peoples accounts.

WOW, its like you didn't even read my preemption. as an INDEPENDENT FACTOR, get it? And those molecules are all so much similar, that of course, the dynamics of heroin (v/s codeine and morphine) greatly outweigh this one factor. Please read b4 u post

 

[Smyth]

Well in short I dont agree with your theory. On one level I dont agree with the general tenet laid out since I think that factors such as speed of onset and duration are more important than potency. I also think that you have your wires crossed in thinking high potency is a bad thing. High potency in an opioid might be a dangerous thing but in terms of euphoria it certainly shouldnt be detrimental.

In fact according to both parts of your theory, meperidine is the most euphoric opioid out there. Now i'll let the people with 1st hand experience move in and see if they agree with this or not.

 

[vecktor]

an interesting theory, and one which I will think about.
perhaps the key here is that the smaller simpler molecules are less selective in their interactions, and this leads to greater euphoria? having said that the ADME of the compounds is probably the deciding factor here.

 

[sarbanes]

an interesting theory, and one which I will think about.
perhaps the key here is that the smaller simpler molecules are less selective in their interactions, and this leads to greater euphoria? having said that the ADME of the compounds is probably the deciding factor here.

vecktor, thats a very astute observation, and an intuitive place to start. Some trains of thought also believe that more of the simple agonists are also sometimes mild NMDA antagonists on some dimension, and that, depending on the nature of the NMDA antagonism, this combination with u-opiate agonism (lol, funny word) is what helps lead to new levels of euphoria. What is troubling are seeming exceptions to the rule, suck as etorphine, or DHE. Both highly potent, and highly euphoric. But there are far too many compounds which *seem* to follow the general rule to brush aside and ignore. Thanks for the thoughtful input, vecktor!

 

[Morninggloryseed]

Turning this from opiates to PEA psychedelics, there is some correlation between activity and the size of what is in the 4. For instance, with 2C-D/2C-E/2C-P...the length of action and the potency both go up as more carbons are added to the chain. With 2C-B/2C-C/2C-I...the heavier the halo, the more potent the compound.

But you are asking about opiates, so I have nothing worthy to contribute.

 

[sarbanes]

Well in short I dont agree with your theory. On one level I dont agree with the general tenet laid out since I think that factors such as speed of onset and duration are more important than potency. I also think that you have your wires crossed in thinking high potency is a bad thing. High potency in an opioid might be a dangerous thing but in terms of euphoria it certainly shouldnt be detrimental.

In fact according to both parts of your theory, meperidine is the most euphoric opioid out there. Now i'll let the people with 1st hand experience move in and see if they agree with this or not.

Yup, and thanks for your well intentioned contribution to my thread.

 

[sarbanes]

Turning this from opiates to PEA psychedelics, there is some correlation between activity and the size of what is in the 4. For instance, with 2C-D/2C-E/2C-P...the length of action and the potency both go up as more carbons are added to the chain. With 2C-B/2C-C/2C-I...the heavier the halo, the more potent the compound.

But you are asking about opiates, so I have nothing worthy to contribute.

It was very worthy, and who knows, there might be some distant relationship. Any positive and thoughtful posts like yours are very worthy, and I thank you for taking the time to read and commont on what I wrote.

 

[vecktor]

Turning this from opiates to PEA psychedelics, there is some correlation between activity and the size of what is in the 4. For instance, with 2C-D/2C-E/2C-P...the length of action and the potency both go up as more carbons are added to the chain. With 2C-B/2C-C/2C-I...the heavier the halo, the more potent the compound.

But you are asking about opiates, so I have nothing worthy to contribute.

it has been suggested that the 4 group sits in a hydrophobic pocket and that the more hydrophobic the 4 sub the more energetically favourable the interaction with the receptor, leading to higher affinity and intrinsic activity, until the group gets too big to fit in the pocket. whether 2C-At would be too big no one will ever know.
the outer limit could be explored with the homologs of 2c-ef which is bromine sized, and then longer chains. I can't work out the sized but 4-(fluoropropyl) should be bigger than Iodine and somewhat similar to the impossible astatine compound.

 

[MattPsy]

there is ith 2C-B/2C-C/2C-I...the heavier the halo, the more potent the compound.

Well, kind of. The trifluoromethyl derivatives are more potent, and they're certainly not heavier than a bromo substituent! It's more about the electronegativity and hydrophobicity I think.

If anyone wants to test this large molecule thing, try the -14 cinnamyl ester of oxycodone perhaps (should be easy to make, too). Apparently, the potency is increased some 70 times, and then you'd have a big fuckoff molecule to test the theory with. (And it'd be fun)

 

[vecktor]

Well, kind of. The trifluoromethyl derivatives are more potent, and they're certainly not heavier than a bromo substituent! It's more about the electronegativity and hydrophobicity I think.

If anyone wants to test this large molecule thing, try the -14 cinnamyl ester of oxycodone perhaps (should be easy to make, too). Apparently, the potency is increased some 70 times, and then you'd have a big fuckoff molecule to test the theory with. (And it'd be fun)

I'm curious is it hydrolysed in vivo and thefore more of a lipophilic prodrug? there are quite few large ester prodrugs with increased potency, basically due to the increased lipophilicity (octanol water partition coeff)

 

[sarbanes]

Also, I've heard many say the O-methyl ether analogs of the corresponding morphines (like codeine v/s morphine, oxycodone v/s oxymorphone), have more jangle and get you more "stoned" (completely aside from the effects due to the o-desmethylated metabolite). If thats true, then oxycodone, which is less potent than oxymorphone, would be expected to be more stoning or more euphoric, at equivalent doses (equalised to compensate for relative potency differences.) And if that is the case, would fit in nicely with my hypothesis.

 

[fastandbulbous]

I can't work out the sized but 4-(fluoropropyl) should be bigger than Iodine and somewhat similar to the impossible astatine compound.

A tad off topic, but isn't it the effect it has on the pi electrons (coupled with it's lipohilicity - is that a word? ) of the the aromatic ring, as MattPsy suggests. The logical larger group would therefore be a 2-fluoropropyl on the 4 position.

With the opioids, there doesn't seem to be much rhyme or reason that's obviously apparent regarding the euphoric potential as dipipanone is way more euphoric than methadone (as evidenced by the abuse potential of diconal), but all that changes is the amine group substitution pattern. With the methadone series I'd say it looks more like the lipophilic properties of the amine substituents (if that's the case then phenadoxone - dipipanone with the piperidine ring replaced by a morpholine ring - should also be very euphoric. Anyone ever come across this drug?).

Thje NMDA antagonism seems a bit haphazard as well seeing as how methadone, ketobemidone and oxycodone all show some degree of NMDA antagonism, yet have nothing else in common other than being mu agonists (incidentally, ketobemidone is supposed to be the pinnacle of euphoric opiates).

If I had to postulate on the euphoria inducing potential, I'd say it's likely to be linked to the 1-octanol:water partition coefficient which gives an indication of how fast it'll penetrate the blood brain barrier

 

[leungkachong]

The most promising idea out of this thread is the idea that something which binds indiscriminately at many-a-site may produce a more subtle/intricate effect (which I also think would probably go along w/ an increased risk of toxicity).

But you guys are looking at the whole wrong side of the coin by postulating a SAR between a cognitive effect and a chemical property. Structure-activity relationships are between receptors and ligands. Alchemy (as the old dudes saw it, not as an idea) is dead. We already know that chemicals do not equate to concepts.

The euphoric potential, as far as science can say, is related (in the case of opioids) to complex pharmaco -kinetic, and -dynamic interactions which impact their resultant disinhibtion of GABA neurons (which express mu-opioid receptors) that usually inhibit/keep in check the DA neurons in the VTA (ventral tegmental area).

 

[sarbanes]

The euphoric potential, as far as science can say, is related (in the case of opioids) to complex pharmaco -kinetic, and -dynamic interactions which impact their resultant disinhibtion of GABA neurons (which express mu-opioid receptors) that usually inhibit/keep in check the DA neurons in the VTA (ventral tegmental area).

Can't argue with that, its absolutely 100% true. So, let me see if I understand what your saying. Even if there was a relationship, it would be coincidence, and nothing meaningful. Yeah, could very well be. Yours is the single best post (next to mine of course, LOL) in this entire thread - tnx

 

[fastandbulbous]

The euphoric potential, as far as science can say, is related (in the case of opioids) to complex pharmaco -kinetic

Well not that complex, BBB penetration seems to be very important w.r.t. how euphoric a drug is. The increased lipophilic nature of diacetylmorphinr compared with morphine gives that indication. Modifications of structures to give higher receptor affinity can push the 1-octanol:water distribution either way hence some drugs with very high affinity not being that euphoric because of slow BBB penetration (and vice versa)

 

[theWorldWithin]

I think the main problem here is that we are trying to make blanket statements about opiates/opiods in general as if they were PEAs or tryptamines. There are so many classes of chemicals with mu agonist properties that the discussion really needs to be broken down to opiods with similar structure then we can start discussing relationships within those subclasses of mu agonists.

 

[sarbanes]

I think what I took away from leungkachong's post, is that, once you have at least several factors (variable) at play, you begin to get hundreds of thousands of different combination potentials, and modeling that would be very difficult unless we can map everything. There are probably some subtle, highly specific things going on that we never dreamed of. There are probably thousands of flavors of opiate euphoria alone, not to mention all other drugs/receptors. leungkachong's comments really hit home for me, and made me realize how futile and overly simplistic my hypothesis probably is.

 

[raybeez]

There are probably thousands of flavors of opiate euphoria alone, not to mention all other drugs/receptors.

I found your hypothesis interested, but want to expand on what your saying here (above). Euphoria is a subjective response, compared to analgesia which can be measured objectively. Opiates that produce euphoria in some users produce either no euphoria or sometimes even dysphoria in others. Some opiates are even gender specific when it comes to eu/dysphoria reactions. Kappa agonists and mixed mu ag/antagonists like Nalbuphine come to mind.