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Novel opioid with Ki of 0.21

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Jordan AD, Orsini MJ, Middleton SA et al. (2005) 8-(Heteroaryl) phenalkyl-1-phenyl-1, 3, 8-triazaspiro[4.5]decan-4-ones as opioid receptor modulators. Med Chem 1:601–610

I haven't calculated the pKa or LogP of this compound but simpler derivatives are covered by:

E. K. Fifer, W. M. Davis, and R. F. Borne, Bur. 1. Med. Chem. 19, 519 (1984).

Now the simpler compounds have a chiral methyl side-chain on the N-benzyl and their potency is x450 pethidine.

These compounds are discussed in 'Opioid Analgesics: chemistry and receptors' by Casy & Parfitt. This work, along with 'Opiates' by R.lenz et al are really vital pieces of work. Even so, there are whole classes of opioids that they don't cover. I've come across some unexpectedly potent opioids. That is what makes opioid chemistry so interesting. The sheer volume of different compounds means it is almost impossible to cover them all and it's very hard for anyone to read the IUPAC and devine the activity.

Many moons ago someone mentioned a new delta/kappa opioid (with reference) that had a secondary amine and an amide. It was open-chain and looked worth more examination but I've lost the paper.

I will finish by noting that BDPC is turning up. From what I have read, it's quite good for 4 hours then just odd for 8 hours. I suspect that it's due to N-demethylation. Why people didn't simply make the p-Me homologue, I don't know. That methyl offers a convenient point for the body to metabolize the material an so while duration is shorter, the action is positive, not mixed.
 
As far as opiods go, natural morphine is still my go to, much more euphoric and less sedating, with an euphoria that is also in the body (hands and forearms mostly) with less side-effects and far from addictive if consumed recreationally in the form of opium or poppy, or simply fentanyls, with which you know what to expect. Opioid receptors are very tangible, like efteling's trashcans that beg for paper but get fed plastic, at least that's starting to be my view with all these opioids that are active but far from pleasurable. A trip report about BDPC is available on Erowid, it describes it as non-water soluble, dull and without any warmth, which isn't surprising given its structure.
 
Hello,

I am sorry if I am posting in the wrong place but I am brand new to this forum and want to post a question for some help.

Can someone help me as where to start at if I want to make a general post in this forum for help with opioid addiction ?

Thank you !
 
Bice said:
Hello,

I am sorry if I am posting in the wrong place but I am brand new to this forum and want to post a question for some help.

Can someone help me as where to start at if I want to make a general post in this forum for help with opioid addiction ?

Thank you !
Click to expand...
Hi Bice,

You should post a the thread in the forum "Health and Recovery".

Welcome to the forum!
 
Gaffy said:
As far as opiods go, natural morphine is still my go to, much more euphoric and less sedating, with an euphoria that is also in the body (hands and forearms mostly) with less side-effects and far from addictive if consumed recreationally in the form of opium or poppy, or simply fentanyls, with which you know what to expect. Opioid receptors are very tangible, like efteling's trashcans that beg for paper but get fed plastic, at least that's starting to be my view with all these opioids that are active but far from pleasurable. A trip report about BDPC is available on Erowid, it describes it as non-water soluble, dull and without any warmth, which isn't surprising given its structure.
Click to expand...

Indeed - M is still considered to be 'the gold standard'. I read an interesting paper in which a double-blind study showed that users couldn't tell the difference between M & H. I do not remember if it was IM, SC or IV but although the users took more M, the study showed that nobody could tell.

As you know, diamorphine is inactive, it's 6-MAM that is the active. Now I remember a researcher who modified a benzomorphan to use as a treatment for cocaine addiction. I don't remember the details but the KEY bit of information for people like us is that he replaced the phenolic -OH with a carboxamide moiety. He even wrote up a 2-step reaction to convert the -OH to a C(O)NH2. The affinity of the carboxamide was slightly lower but the LogP was slightly better so the compounds were equipotent.... but the important bit? With the phenol, the T1/2 was about 150 minutes BUT with the carboxamide moiety it was about 480 minutes.

I do not see anybody in the mould of 'The French Connection' going for this BUT if it means that the M or 6-MAM analog of morphine lasting so long, it might make it a much more useful drug to help those dependent on opioids.
 
clubcard said:
BUT if it means that the M or 6-MAM analog of morphine lasting so long, it might make it a much more useful drug to help those dependent on opioids.
Click to expand...

Since you talk of isomerism at the 6 position on morphine elsewhere, I think of heterocodeine for one. Any isomers of codeine that're active?
 
draculic acid69 said:
Heterocodeine is 6methylmorphine.6x stronger than morphine
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Table 3-3 on Page 63 of 'Opiates' by R.Lenz details the relative potency of morphine analogues with the moiety at the 6 position changed & the position of the alkene changed.

A 6 methylene is x60 M. A Wittig reaction from a =O yields 53%.

What is not detailed is the addition of a 14-OH or indeed the 3,14-diacetyl derivatives. Even further afield, nobody has tried altering the 6 and the N. I mean,an N 2(2-furyl)ethyl is some x60 of the parent N-methyl so it's very tempting to wonder just how potent the phenanthracine analogue bearing BOTH those modifications would be.... and just for peak stupid, just like the fentanyl class, an (S) beta hydroxy on the ethylene spacer increases potency even more! Still, x3600 would be both interesting and frighteningly dangerous.
 
Ah - Janssen discovered the simpler analogues back in the 1960s. The N-benzyl is the most active BUT it has to have a methyl side-chain to prevent rapid metabolism.

Sadly, Sci Hub doesn't have the paper cited. I'm not going to spend $65 only to discover that it's a waste of time.

What I suggest is that the 2-(2-thienyl)-benzyl moiety places the thienyl at the precise position required for mu affinity. After all, the rest of the molecule is simply a rigid fentanyl derivative. I am prepared to bet that this is rather potent and totally impractical to synthesize. Interesting though!
 
Ik denk niet dat hij Nederlander is, koop prullenbakken voor pretparken met die heerlijke geur van braaksel, gebruikte luiers en weggegooid fastfood... Febo, denk ik.
 
BTW I checked the physical properties of the image in the first post. It overlays thiofentanyl & C-8813 but it's more rigid. I found the patent and noted that he paper remarks ' Substitution on the biaryl moiety produced enhanced affinity for the mu-opioid receptor.'

Of course, the patent gives DOZENS of different substitution patterns to the biaryl group. The KEY thing is that the relative position of the piperidine ring's N (and lon-pair orientation), the thiophene-ring, the 1,3,8-spiro's benzene & the amide moiety are all close.
 
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