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Opiate Receptor Mechanisms - book

Library Genesis

libgen.li libgen.li

This will open a couple of ad windows but on the third try (at most) you can download the .PDF of the book 'Opioid Analgesics - Chemistry and Receptors' by Casy and Parfitt
 
Although you said no synthesis discussions are allowed, the Bromadol synthesis in this book describes the PCP method of synthesis that is not available in the literature, and is only theoretical conjecture. Note that the actual synthesis pathway described by Lednicer is included here (for theoretical interest only).
 
Smyth2 said:
Although you said no synthesis discussions are allowed, the Bromadol synthesis in this book describes the PCP method of synthesis that is not available in the literature, and is only theoretical conjecture. Note that the actual synthesis pathway described by Lednicer is included here (for theoretical interest only).
Click to expand...

I think you asked this before.

It's my understanding that their is a loophole in US Federal Law so PCP is being produced at scale in a single step. Yield is almost quantitative. No controlled precursors are used.

Due to many factors, it's actually simpler to perform a large-scale synthesis than a desktop synthesis. By scale I mean 208.2l reaction vessels and a pipeline where multiple batches are begun an hour or two apart so that in a week, the 'cook' has rather a lot of product.

Every report I read says PCP is awful and it's certainly addictive so something I suggest is best avoided if your ethos includes not knowingly harming others.
 
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Not actual pcp itself but the 1,4-dioxaspiro[4.5]decan-8-one is reacted to bromadol via a pcp/carfentanil Strecker-type α-aminonitrile.

The method is in the Lenz book so it's not like it is just me saying it. Although this is not the actual quoted literature proecedure reported by Lednicer.
 
Well, in drug descovery the only yield you need is 'enough' and it isn't particularly price sensitive.

I think the cheapest route yielded the monomethyl amine which one then had to selectively methylate. Since then new variations of the Eschweiler-Clarke reaction have been developed. So I imagine the cost wil have dropped.

But as a target, BDPC reports are not too good. First 4 hours 'OK', next 8 hours 'not nice'. Yeah, well MDPC would likely solve that issue as the p-Me is labile so N-demethylation isn't the main metabolic pathway but I suspect all you get is an 'OK' that lasts for 3-4 hours.

But we lack human trials, the sheer potency and that 'OK' leading people to consume more looking for the euphoria all add up to a killer.

That's incompatible with our ethos.

Not killing people has a higher priority than money.
 
I wonder if the QSAR is like for Diclazalone where the p,m-dichlorophenyl analog is the one with the strongest affinity to the receptor.
pubchem.ncbi.nlm.nih.gov

PubChem

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No.

Or, rather I should say that earlier work showed that the p.m-dichloro homologue of dimetadine was almost inactive.

Why the p-Br and p-Me of all things should prove to be so active is still something of a mystery. But I'm pretty sure Dan was thorough.

The only class of opioid with a benzylic tertiary amine and a p,m-disubstitution is the metofoline class. I looked and examples with only a p substituent were active.

The 3-phenyl-3-dimethylamino propanamide class lacking a m -OH ARE agonists but I bet you £1 that IF agonist activity can be increased by ring substitution (of the N,N-dimethyl derivative), it will be p mono-substitution. I mean, overlay the two classes in ChemOffice and you will see what I mean. But never forget - every example demonstrates stereoisomerism of some sort. But as far as I know, the (R) enantiomers are always the active. So right of the bat you are going to get poor yields.

And who knows what the toxic profile of the actives are, let alone the unresolved products.
 
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That's interesting that you are prepared to bet £1 on it since it seems like a sensible QSAR structural analysis.

Note that for pcp the para,meta-dichlorophenyl ring substituted analog was never seen and all that appears is BTCP & GK-189 [81490-58-6].

I checked the Berndt Sundermann patents for Gruenethal and they are doing the pcp-esque synthesis of bromadol that is so different from the Lednicer protocol reported at Upjohn.

Bernd Sundermann, Hagen-Heinrich Hennies, Werner Englberger, Stephan Wnendt, US7183436 (2007 to Gruenenthal Gmbh).
Bernd Sundermann, Hagen-Heinrich Hennies, Werner Englberger, Babette-Yvonne Koegel, US7211694 (2007 to Gruenenthal Gmbh).

By the way, what is dimetadine?
 
en.wikipedia.org

4-Dimethylamino-4-(p-tolyl)cyclohexanone - Wikipedia

en.wikipedia.org en.wikipedia.org

Dimetadine - Dan tried HUNDREDS of ring substituents but he didn't bother including those that had no activity whatsoever. But while the p-Br and p-Me were active at 3mg/kg, the p,m dichloro is something like 66. I haven't read the paper in decades so those numbers may not be accurate - but the ratio is pretty accutate.

A much better qhestion is WHY in that case the p-Br and p-Me were so much more active than all the others while in the U4 class (also Dan - he handed it of to Jacob once the ring substitution was proven), it's the p,m disubstitution. The p-Br homologue IS known - https://en.wikipedia.org/wiki/Bromadoline

So ask in each case what the ring-substitutions are ACTALLY doing.

Of the 3-phenyl-3-aminopropanamide class I mentioned https://sci-hub.ru/10.1016/s0960-894x(00)00034-2 we have another potent ligand with a chirak benzylic amine and the same enantiomer is the active. There are about a dozen example of these odd 'reversed HBO/PIF' opioids all the way from the weak (doxicopamine - check the. Homologues are more potent and no not mixed agonists) through https://en.wikipedia.org/wiki/Ciramadol , https://en.wikipedia.org/wiki/Metofoline (and derivatives - read all patents) all the way through https://en.wikipedia.org/wiki/BDPC homologues and on to the 3P3A class.. Even the https://en.wikipedia.org/wiki/Diphenpipenol1 derivatives might be tought of as posessing a benzylic amine. In this last one, IUPAC naming means the (S) overlays the (R) of all the others. Try removing the phenolic aromatic from https://en.wikipedia.org/wiki/Diphenpipenol and it would appear that likewise, it's still a MOR ligand. I judge it only to posess modest MOR agonist activity but it is another example. Likewise https://en.wikipedia.org/wiki/SNC-80 derivatives.

Hard to know if the arylcyclohexylamine class have significant MOR affinity although one of those books describes a derivative that is.

But the 3-phenyl-3-amino propanamide class are mostly ANTAGONISTS. but remove that meta phenol and you have an agonist. swap the secondary amine for a tertiary (dimethyl) amine and you have a more potent agonist. It's still not THAT potent but when we look at the ring substituents. Experience suggests that the p-Me would be the synthetically simplest to test but if I HAD to guess, I suspect that for that scaffold, a p-F might be the most potent - I did upload a link to a largely unknown/untested/ow potency class of MOR ligands that were 'reversed; and were closer to the 3P3A class and as the p got bigger, potency went down. But I suggest that just like BDPC one has to first establish if p monosubstitution, p,m disubstitution or even o monosubstitution,

It's not like we can't build a reasonable training set. What we cannot build is a GOOD training set. I just do not consider any of the targets to be of utility. It may be the case that the 3P3A class has niche uses in research... but either it's just not THAT potent so not facile or it is which means it would kill people.

Maybe I missed some examples so if you can find more examples of MOR ligands with a benzylic tertiary amines, the more we have, the better any training set would gets.

BTW https://en.wikipedia.org/wiki/Diphenpipenol exhibits two distinct types of isomerism. The o-MeO ensures that the aromatic is at a specific rotation angle relative to the piperizine. The lone pairs of the O and N will ensure that. But resolution? Who knows? I would class that as a rotatomer alrhough is it closer to atropisomism. I do not know.
 
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pubchem.ncbi.nlm.nih.gov

5-(Dimethylamino)-4,4-dimethyl-1,5-diphenylpentan-1-one

5-(Dimethylamino)-4,4-dimethyl-1,5-diphenylpentan-1-one | C21H27NO | CID 200902 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov

Oh - anotherone from the book (one of them, anyway). I have uploaded the references elsehere. It's journal artiels rather than patents. BUT I consider it to be the prototype of the 3-phenyl-3-aminopropanamide class.


Sadly the synthesis emplyed meant ring substituting just the A ring was not possible.

But I assume your database might turn up more examples.
 
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Smyth2 said:
it links to these documents:

[1] J. Med. Chem. 1966, 9, 2, 187–191, https://pubs.acs.org/doi/pdf/10.1021/jm00320a007
[2] WILSON, A., PIRCIO, A. Narcotic Analgesics: Possibility of Broadening the Structural Basis of Analgesics. Nature 206, 1151–1152 (1965). https://doi.org/10.1038/2061151a0
[3] Kuna Samuel & W. Pircio Anthony, CA830475 (1969 to Bristol Myers Squibb Co).
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I kept adding links to my first post just to save you some time and effort - no point in re-inventing the wheel (unless you find a patentable use-case). Hope it helps.
 
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