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And just for a change, here's one that is known to work. The methylene bridge places the N: in the same relative position to the aryl as the aryl:methylamine of nortilidine. Of course, it's fun, fun, fun to make but it IS very rigid and so it's affinity is pretty decent. I cam across it in a 1960s German paper on tilidine and related compounds. Always remember that it isn't the N but the N: position & orientation is what matters. That is why unusual compounds like dezocine are primary amines and why they are mixed agonist/antagonist.
MANY years ago researchers produced quaternary salts of common opiates like morphine so, in practice there was a chiral centre and it turned out that 1 isomers was an agonist, the other was either an antagonist (phenol or bioisostere thereof) allowing.
I find it interesting because it showed that some keen medicinal chemists asked a simple 'what if?' and proved it to be true.
Secondary amines usually have a conformation that places the N-alkyl opposing the N: and so they turn out to be agonists. Above you will note an example of a secondary amine. I suspect it is a total bitch to make and some poor post-grad student ended up as an 'et al' even if it took them a year.
You will note that like tramadol (also a DRI/NRI without the ester) is closely related. I think I have pointed out that it is possible to produce a highly EUPHORIC opioid (due to DRI action) based on some quite average DRI/NRI lligands.
Since lat post I've had the chance to try the N-methyl homologue of isopilidine. It lasts for a good 6 hours. It is highly euphoric so all I can say is that people do NOT try to find a regular dealer. I've seen chemist/users who were obtaining bottles of the stuff and converting it to something very similar,just x10 more potent.
Of course, it's the DRI/NRI action that makes it different BUT I do not know IF it has NMDA activity, someone could make billions. Now, think about that - if dealers make billions, WHO LOSES.
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Nowm, I admit that I have suggested MANY terminal aryls (based on Lednicer's work) but while not being the compute, Lednicer mentioned this as a more practical, longer-acting analogue. The KEY is that usually the aromatic is hydroxylated but with many 5-membered heterocycles, this isn't possible. The 2-thiophene analogue was known and tested and turned out to be x267 (rather than x204 for the parent.
Of course, the key is NOT to rely on aromatic hydroxylation because it is not relaible between to patients. Yeah, we could make it VERY hard to metabolise, but something x504 REALLY does not need modification.
If you must play, swap the phenolic -OH of morphine and derivatives to a carboxmide which has a MUCH longer duration.
We may also do well to look at the methadone analogues, Several were noted as being 'moreish' i.e. people took for fun, tot for main.
Well, whatever, expect hydromorphone analoguse very soon. JUST ABOUT kitchen chemistry and fuck, it it's x10 H, EVERYONE will be at it.