But Slappy, there must be some relatively selective kappa and delta opioid agonists, right? If almost all the classic effects are mediated via the µ-receptor, what does relatively selective kappa/delta agonists feel like? Or are there none that selective found yet?

Rhodium,

Check this paper out:  J. Med. Chem. 2002, 45, 537-540

This paper is excellent, has info on some really cool oxycodone congeners with VERY high kappa and delta receptor affinity and little mu agonistic activity.  There is also an analogue with extremely high Mu affinity, it is an adduct of B-nitrostyrene(isn't that cool!)  and N-Benzylimino-oxyxocone.  It's a simple procedure with a decent yield.

I can post the .PDF on request.

There are a whole slew of agonists selective fo the delta and kappa opioid receptors, just look in your Sigma or Tocris catalog or the like. There are many ligands with >nM affinity for a certain receptor subtype even. Most of the opioid ligands are peptides, like our endogenous µ-agonists, the Endomorphins, or Deltorphin for the kappa. Some examples of specific non-peptide agonists are: SB 205607, SNC 80, SNC 121 (delta) and BRL-52537, ICI 199,441, N-Methyl-N-[(1S)-1-Phenyl-2-(1-pyrrolidinyl)ethyl]phenylacetamide HCl, (-)-U-50488, U-54494A (kappa). All three receptors also have a variety of selective antagonists.

As you can tell, these are all experimental probes for neuroscience research. A delta or kappa agonist would never be commercialized, at least not as an analgesic, because they just don't posses those properties. Many opiates on the market posses delta and kappa agonizing properties, but that is just peripheral to the µ action.

There is also one more opioid receptor, the Orphan Opioid Receptor ORL₁ (Opioid Receptor-Like₁) that has a high degree of homology with the mu, delta, and kappa receptors, but a distinctly different pharmacological profile. i.e., it looks and acts like the other opioid receptors, but doesn't produce any effetcs that would normally be attributed to that family other than adenylyl cyclase inhibition.

I have ingested a selective kappa agonist before, and the only effects it seemed to produce was a slight headache and nausea.

You can tell me.

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crazyredhead
03-25-02 23:01

Post 287764 (missing)

(crazyredhead: "Massive Renovation In Newbee Forum", Newbee Forum)

Massive Renovation In Newbee Forum  

Third rule -- No discussion of ongoing or planned criminal activity. This board is a place for learning "theoretical" synthesis. A simple guideline for appropriate posts is to always keep them impersonal and timeless. For example  "swim dreamt about another life where he........."

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Pleasure me.          

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You've gotta love me.

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slappy
(Hive Bee)
03-28-02 00:03

Post 288698

(slappy: "Hmmm... no.", Methods Discourse)       

To answer your question, no. There are times for alcohol, and there are times for aprotic solvents.

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Damn,I really need glasses. You had answered my question and I missed it.
Thank you Slappy. I think I was stil sleepy because I had just wake-up when I read your post. Sorry, my mistake.      Crazy me         
 

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You've gotta love me.

Slappy said: Well, we know that Fentanyl gives a rich, heroin like high. And many people think that it is much more euphoric than Heroin even.

Well, I disagree.  Morphine is more euphoric than fentanyl.
What few people know is that fentanyl is actually less addicting.  The withdraw is not as tough as with morphine / heroin, probably because the dose is so small (and because it is not as good).  The only fentanyl that could compete with heroine is probably 3-methyl fentanyl.  The narcotic effects have about the same duration as heroin (4 hours).  The long duration is due to the pseudo irreversible binding to the receptor.
Furthermore, a positive thing however is that fentanyl does not induce such a histamine release as morphine.

Slappy's article (cfr supra

Post 285252

(slappy: "'Re: Easiest way to amphetamine in the kitchen+Fen", Methods Discourse)) is available here:

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-Acting Opioid Analgetics
Paul L. Feldman, Michael K. James, Marcus F. Brackeen, Joanne M. Bilotta, Suzanne V. Schuster, Avis P. Lahey,
Michael W. Lutz, M. Ross Johnson, and H. Jeff Leighton

J. Med. Chem. 34(7), 2202-6 (1991)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/ultrashort.ultrapotent.fentanyl.pdf)

_{Abstract
In an effort to discover a potent ultrashort-acting p opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of Canilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent p opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(l-oxopropyl)phenylamino]-lpiperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for p opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent p agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterases. The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.}

Despite my disinterest in opiates as recreationals, this thread has been a VERY interesting read.


Ritter, please, post that PDF!



Yours,


Antoncho

Ritter's find from J. Med. Chem. 2002, 45, 537-540 is now available here:

4'-Arylpyrrolomorphinans: Effect of a Pyrrolo-N-benzyl Substituent in Enhancing sigma-Opioid Antagonist Activity

https://www.thevespiary.org/rhodium/Rhodium/pdf/4-arylpyrrolomorphinans.pdf

The development of selective antagonists for mu, sigma, and kappa opioid receptors has allowed both the role of these receptors to be defined and the selectivity of agonists to be determined. The functions in which  receptors are implicated are quite varied. sigma Agonists were first of interest as offering analgesia without the problems associated with the traditional mu agonist analgesics, e.g., morphine. But sigma agonists also have antidiarrheal effects without affecting gastric mobility and are immunostimulants and stimulants of respiration. sigma Antagonists are immunosuppressants and prevent the development of tolerance and dependence with mu agonists so that opioids with mixed mu agonist, sigma antagonist profiles have beeen recognized as having potential as analgesics for the relief of severe pain.

What few people know is that fentanyl is actually less addicting.  The withdraw is not as tough as with morphine / heroin, probably because the dose is so small (and because it is not as good).

This also in contradiction with what has been written in post

Post 347651 (missing)

(raffike: "Actually fentanyl and it's analogues cause harder ...", General Discourse):
Actually fentanyl and it's analogues cause harder addiction than H cuz it's said to be better than ol' brown H


I just wanted to straighten this out.  Again, just because a compound is more powerfull (lower ED₅₀) it doesn't necessarily imply that it is better and / or more addictive.

Furthermore, p-fluoro-fentanyl seems to be more morphine like than fentanyl.
The order of receptor affinity of morphine is mu > delta > kappa, whereas in fentanyl and sufentanil the order is somewhat reversed (mu > kappa > delta).  p-fluoro-fentanyl has the same order of binding affinity to the receptors as morphine, with the only difference that it binds
49 x stronger to the mu receptor,
7 x stronger to the delta receptor,
and 5 x stronger to the kappa receptor
than morphine.

For comparison, fentanyl binds
7 x stronger to the mu receptor,
0.9 x stronger to the delta receptor,
and 2.8 x stronger to the kappa receptor
than morphine.

And sufentanil binds
24 x stronger to the mu receptor,
3.7 x stronger to the delta receptor,
and 14 x stronger to the kappa receptor
than morphine.

So, p-fluoro-fentanyl is stronger than sufentanil.
And o-fluoro-fentanyl is even stronger than the para isomer.  That compound would blow the crap out of you, even by looking at it ...

Who said p-fluoro-fentanyl is weaker than fentanyl ... hmm let me see.

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Maintenant, je suis cassé                 ggrrrrrr ...