Pharmacology Opioids - 3 aromatic rings (or at least fragment of a third)

[AlsoTapered]

Anybody else noted that norbezitramide has 3 benzene rings and is x20M. Allylprodine has a fragment (an allyl) of a second aromatic and is x4 prodine and crazy things like R-4066 (a methadone derivative) is x212 M? Or 4-phenyl fentanyl x6400 M.

I kept saying that nobody had listed all the key moieties,

1-benzene ring (a)
2-benzene ring (or fragment) (b) 2-3 methylenes from 2
3-aromatic ring 6-7 methylenes from (a)
4-Positively ionizable function
5-hydrogen-bonr donor
6-hydrogen-bond acceptor

There are also small side-chains (like in 3-methyl fentanyl/prodine) that are not fully understood but most papers guess 'increase molecular recognition. In fact, they just allow the compound to lose more energy as they bind to receptor i.e. increases affinity,

So not there quite yet... but getting closer every time.

 

[MedicinalUser247]

Well you got your work cut out for you there because there's over 1400 fentanyl analogs know to exist over all.

 

[AlsoTapered]

Well you got your work cut out for you there because there's over 1400 fentanyl analogs know to exist over all.

You seem to have failed to understand the point being made I gave examples of a number of classes that contain all 3 aromatics and as I pointed out, compared to the analogues lacking them, they are much more potent.

When I mention 'fragment' I mean an allyllic group because like an aromatic group, they have pi bonding (p-orbital that is conjugated with the adjacent pi bond).

By all means question - but if you don't understand the original statement, don't presume to correct people. Believe it or not, you are NOT an organic chemist and much less a medicinal chemist. I have always tried to fairly and reasonably correct your mistakes and to explain misunderstandings. For a start, you should have looked at all the compounds I named to see the commonality.

Your statement just underlines the fact you should be making at least SOME effort yourself. Note that 32 other people also read the thread and none of them felt justified in correcting me. It's not like I'm the most qualified person here, but I did study the subject for 8 years formally and informally.... 27 years.

 

[MedicinalUser247]

As far as I know carfentanil or (4-methoxycarbonyl)fentanyl is the strongest opioid known so far. A lot of opioids are related to morphine which have the features your talking about which include 3 rings, 5 rings and 6 hydroxyl groups, alcoholic and phenolic, an a piperidine ring that has a N-methly group an a quaternary carbon at position 13. Morphine can be modified in many ways. Fentanyl can be modified much more. That's why I stated that there are over 1400 analogs. If you wanted to create something stronger or more euphoric instead there are many ways to do that. It all comes down to your own hypothesis. I didn't mean to offend you in any way and I have the utmost respect for you.

 

[AlsoTapered]

As far as I know carfentanil or (4-methoxycarbonyl)fentanyl is the strongest opioid known so far. A lot of opioids are related to morphine which have the features your talking about which include 3 rings, 5 rings and 6 hydroxyl groups, alcoholic and phenolic, an a piperidine ring that has a N-methly group an a quaternary carbon at position 13. Morphine can be modified in many ways. Fentanyl can be modified much more. That's why I stated that there are over 1400 analogs. If you wanted to create something stronger or more euphoric instead there are many ways to do that. It all comes down to your own hypothesis. I didn't mean to offend you in any way and I have the utmost respect for you.

Yes - because they contain some of the OTHER key moieties I pointed out. If you didn't know their meaning, you could have SO EASILY Googled them. You see - I PRESUME people have some knowledge or they will realize they don't have the knowledge and make the effort to acquire it. R-30490 is listed as the most potent fentanyl analogue BUT nobody had made the beta-hydroxy derivative (which would have the hydrogen-bond donor), for example, but when you get to roughly >x1000, how potent the opioid is in vitro varies from person to person. Nobody can say it's x 300000 M because the effect will vary HUGELY between individuals.

Please, learn some medicinal chemistry. If it was a valid point and I had made a mistake I WOULD like to know. But to be wrong and then & after correction, continue down the same path, ignoring the response is just lazy.

It won't be a problem for me - do it again and I will simply block you. You can't teach someone who BELIEVES they know better so it would be a waste of both our times.

 

[Skorpio]

Hey @AlsoTapered, can you be a little nicer about this stuff? People here have all kinds of different backgrounds regarding medicinal chemistry, and chastising people for not upholding your standards is counterproductive. Let people learn to like chemistry rather than chasing them away, innit.

 

[AlsoTapered]

Hey @AlsoTapered, can you be a little nicer about this stuff? People here have all kinds of different backgrounds regarding medicinal chemistry, and chastising people for not upholding your standards is counterproductive. Let people learn to like chemistry rather than chasing them away, innit.

I'm free to block whomever I choose am I not. My first response was MUCH milder because the person had clearly missed the point.... and then they compound the error because they apparently didn't look at the compounds I suggested and plowed on STILL failing to grasp the point.

On other threads I have gone to a lot of time and trouble to REALLY explain the QSAR and yet it seems that I put in the effort, they don't. So it's not like I snapped after 1 post - I spent about 3 hours providing them with information (all checked and reffed) and didn't even get a thank you.

So yes, maybe I am being snappish - but you cannot teach someone who doesn't want to learn. It's a waste of time for both parties. I'm not angry, just a bit annoyed that I put in so much effort for someone who doesn't want to learn.

Sorry.

 

[Smyth2]

As far as I know carfentanil or (4-methoxycarbonyl)fentanyl is the strongest opioid known so far. A lot of opioids are related to morphine which have the features your talking about which include 3 rings, 5 rings and 6 hydroxyl groups, alcoholic and phenolic, an a piperidine ring that has a N-methly group an a quaternary carbon at position 13. Morphine can be modified in many ways. Fentanyl can be modified much more. That's why I stated that there are over 1400 analogs. If you wanted to create something stronger or more euphoric instead there are many ways to do that. It all comes down to your own hypothesis. I didn't mean to offend you in any way and I have the utmost respect for you.

Lofentanil is more potent than carfentanil and also has an much longer duration of action.

The current world record holder for the most potent fentanyl analog is Ohmecarfentanil.

para-fluoro ohmefentanyl is 17958 times more potent than morphine. https://pubmed.ncbi.nlm.nih.gov/12779044/

If I had to come up with a world record holder I would make para-fluoro-ohmecarfentanil.

But just because that's the idea in theory, I think it still takes practical work to test the hypothesis.

 

[3DQSAR]

I was under the impression that 14-phenylpropoxy metopon was even more potent. There are several papers by Helmut Schmidhammer that are extremely informative.

I find it interesting that there doesn't appear to be a facile route to forming a methyl ether from 14-hydroxy morphinans. Maybe that's a good thing. I cannot help thinking that IF someone were able to produce a product subjectively like oxymorphone but fifty times more potent, it would not end well for anyone concerned.

 

[emkee_reinvented]

I'm free to block whomever I choose am I not. My first response was MUCH milder because the person had clearly missed the point.... and then they compound the error because they apparently didn't look at the compounds I suggested and plowed on STILL failing to grasp the point.

On other threads I have gone to a lot of time and trouble to REALLY explain the QSAR and yet it seems that I put in the effort, they don't. So it's not like I snapped after 1 post - I spent about 3 hours providing them with information (all checked and reffed) and didn't even get a thank you.

So yes, maybe I am being snappish - but you cannot teach someone who doesn't want to learn. It's a waste of time for both parties. I'm not angry, just a bit annoyed that I put in so much effort for someone who doesn't want to learn.

Sorry.

Maybe you should imagine the ordinary mind, like mine. Just reads Amide

'Trigger' Dextromoramide. And thats as far as my knowlegde goes,
A Master/ Teacher is some one who just knows more thing s then others.
Like you on this topic as example, treat us humble as unknowing kids.
Or in my case, as chemistry/ Opiod infant s.

Just intrigued by dextromoramide.
My pacifier , why there no emticon for that specific Nipple substitute

 

[3DQSAR]

Maybe you should imagine the ordinary mind, like mine. Just reads Amide

'Trigger' Dextromoramide. And thats as far as my knowlegde goes,
A Master/ Teacher is some one who just knows more thing s then others.
Like you on this topic as example, treathy us as kids.
Or in my case, as chemistry/ Opiod infant s.

Just intrigued by dextromoramide.
My pacifier , why there no emticon for that specific Nipple substitute

I don't know what to tell you. I have tasted the compound just twice, the latter experience almost resulted in my death.

To paraphrase the 'Peter McDermott Guide to the Depressants:

'Palfium (dextromoramide) appears to be highly unpredictable. One day you can take 5 pills and be fine. The next day you take 3 and end up slumped in the corner turning blue. Thumbs down'.

The last nation to use dextromoamide was The Netherlands. Now while I cannot be certain, I suggest it's because when consumed orally, dextromoramide has an onset that those who know describe as being very much like IV heroin. Certainly the onset is unexpectedly fast and powerful. I mean powerful to the extent that you really should be sat down.

Palfium is testament to just how thorough research chemists are Janssen were. It's a tiny island of activity in a sea of almost compete inactivity. I would love to know if they had constructed a Drieding model and PREDICTED activity. The second most active is the diethyl amide analogue and it's only about ⅕ the activity, all the others less than half as much again.

I don't know if this is good news, but recently researchers calculated an analogue that may actually be slightly more potent:

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide—A Novel Potentially Powerful Analgesic †

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic...

www.mdpi.com

Now I don't know exactly why dextromoramide has such a rapid onset. Possibly there is an active transport involved. But what I know of Palfium is that most of the people I knew who used it are dead. It never seems to end well.

 

[emkee_reinvented]

I don't know what to tell you. I have tasted the compound just twice, the latter experience almost resulted in my death.

To paraphrase the 'Peter McDermott Guide to the Depressants:

'Palfium (dextromoramide) appears to be highly unpredictable. One day you can take 5 pills and be fine. The next day you take 3 and end up slumped in the corner turning blue. Thumbs down'.

The last nation to use dextromoamide was The Netherlands. Now while I cannot be certain, I suggest it's because when consumed orally, dextromoramide has an onset that those who know describe as being very much like IV heroin. Certainly the onset is unexpectedly fast and powerful. I mean powerful to the extent that you really should be sat down.

Palfium is testament to just how thorough research chemists are Janssen were. It's a tiny island of activity in a sea of almost compete inactivity. I would love to know if they had constructed a Drieding model and PREDICTED activity. The second most active is the diethyl amide analogue and it's only about ⅕ the activity, all the others less than half as much again.

I don't know if this is good news, but recently researchers calculated an analogue that may actually be slightly more potent:

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide—A Novel Potentially Powerful Analgesic †

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic...

www.mdpi.com

Now I don't know exactly why dextromoramide has such a rapid onset. Possibly there is an active transport involved. But what I know of Palfium is that most of the people I knew who used it are dead. It never seems to end well.

It was stolen from the Vault in the medical supply bussiness i had a parttime job.
Not me btw.

No one, officially died, after the theft. It was in the news paper as warning might kids find,
never happened. Probably made a bunch of hard core heroin addicts happy. A while.

Herman Brood took it, loved the rush, but dr s were different then.
You could talk to a doc then about drug addiction withouth stigmatizing yourself.
Those days doc s were allowed to try their own medicine s.

While now becoming a junky means loosing being treated as human.
He forged script s off it as it was as good as heroine.
He got off Heroine with Methadone btw.

And indeed till '98 at least it was prescribable.
But discouraged, with the notification you mentioned, the irredic Pharmakinetics.
But as it is orally portraided as pretty Euphoric. It stuck.

Guessing oral Tillidine or Oxycodone are safer alternatives.

 

[3DQSAR]

Well nortilidine is more likely to have a fast onset. I know Brood stated he had stopped using opioids although in retrospect, the guy was more or less referred to as 'De nationale junkie' and I suggest that people WANTED him to use, even if he felt like he wanted to move on.

I was more upset to learn that Jules Deelder had died. The guy was and is a fantastic performance artist.

 

[emkee_reinvented]

Well nortilidine is more likely to have a fast onset. I know Brood stated he had stopped using opioids although in retrospect, the guy was more or less referred to as 'De nationale junkie' and I suggest that people WANTED him to use, even if he felt like he wanted to move on.

I was more upset to learn that Jules Deelder had died. The guy was and is a fantastic performance artist.

He hated the artisic numbing effects of Opiods, so became speed freak, after kiking the habit, after partying Nina Hagen.
Again became Speed freak and a Alcoholist. Till it endend, Brood and Deelder were pretty close friends.

'De nationale junkie' ment. speed freak alcoholic and toally himself. And loved by even our Queen,
who he would have loved to pent3etraited. He was a also sexual addict.

Btw Brood never was planning to stop, he gave fuck bout peern pressure, just IV-ing Speed had a limit in him,
Stopped working att. The sole reason he stopped, and ended his life to savehimself and people witnissing his decline.


Like em both, both unique, no copy cats, raw, like R_dam is. And transperant, bout drug use the costs and the money.
They not being money collectors or Edophiloe fucks like Combs, honoust junks. Good parents, taken circumstances.

Imo they are equal. They both being last of the real speed addict s, like Lemmy once mentioned.

And cared a lot for their kids. Despite stigmatized as being functional accepted addicts.