• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Novel Opioids

Fertile said:
But here is the thing - I cannot find the N-2-(2-furanyl)-ethyl moiety in any morphinan with an epoxy bridge. Maybe it's just because the more complex (fully synthetic) compounds above were made a decade or more later than the semi-synthetic examples with the bridge.... or maybe the furanyl doesn't work if the bridge is present.
Click to expand...

interesting observation. dont know any opioid expert you could consult.
 
I don't think anyone knows or, rather, all they do is test the activity. From the report, beta hydroxy fentanyl is significantly more potent and since it's the (S) that increases activity.... it might well be applicable in other situations.
 
i think there is a lot still unpublished. maybe only deep down in some big pahrma archive. what about N-arylalkyl bentley compounds? every good lab can test these without problem, surely more toxic than botox but i think they have been made. no paper i found about it. patent search not done, but nothing from bentley i think.
 
Well - the obvious way to check is to draw it up in Chemdraw, convert to SMILES and search Pubchem. I checked and it's not mentioned.

I suspect that LogP and other physical issues come into play when you get something so lipophilic and bulky.
 
US4150135A - 4A-Aryl-cis-decahydroisoquinolines, such as N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, useful as analgesics.

ibb.co

1

Image 1 hosted in ImgBB
ibb.co ibb.co

Another example of a class of novel phenolic opioid in which the N-2-(2-furenyl)-ethyl is the most potent of the series.

Isn't it interesting just how many of these unusual compounds never make it into the scientific literature. One has to find the patent. Still, only 7 million patents to read ;-)
 
Fertile said:
I suspect that LogP and other physical issues come into play when you get something so lipophilic and bulky.
Click to expand...

i once had the idea to put a 2-methoxybenzyl on the N of nor-LSD. maybe there a problem with lipophilicity arises but the benzyl tryptamines were nothing special as i recall. but with lsd theres also the pea backbone incorporated, so maybe more luck there.
 
No - you can place many groups at that 8 position. If you look closely at LSD, you will see it's a superset of the DMT molecule so any tryptamine that is active can share the same N-moiety. So if the methylmethoxy homologue of DMT works, the LSD homologue is also likely to work.

But the biggest issue with LSD synthesis is obtaining precursor. Oh, and that in bulk, it's not worth nearly as much as you might think.

That is why opioids are the class to go for. At the highest level of bulk dealing (like 200Kg of H equivalent) you still get 20% of retail price. By far the highest.
 
Pure fentanyl is only worth $4150/kg at scale. Heroin is worth $6000/kg at scale.

I guess people who pill fentanyl get more for 1Kgs worth, but the US is odd, pills come in bottles. In Europe everything comes in blister-packs (with printing on foil) and often strips of 10 go into boxes of 100. If you bother with proper pills (biconvex, break line, logo) then it's a LOT of work but one can expect to sell a pill worth $10 for $2 even when it's say 200,000 pills in total?

Why? Perceived value. That is why crushable oxycontin was worth ¢50/mg. So if someone make a drug subjectively like oxycodone, an 80mg pill would fetch $80 on the street, $8 in bulk i.e. $10,000/Kg. But that's only when you have superb product and you are the only source.

Now everyone is making fentanyl & etonitazene. The chemistry has been telescoped. But the clever chemist poked holes in the law to make something potent AND euphoric.
 
yeah, every time these orange bottles in us tv series. over here everything gets blistered. also another difference is that in the usa can send commercials about prescribtion medicines like prozac. over here this is forbidden.

tried brorphine on its own lately, was not that impressed. lame opoid, but thats what i hear from all anilinopiperidines. is a proper etonitazene derivate any better? on had metodesnitazene, one of the lamest opioids i had, full dose around 500mg.
 
Someone developed a 1-pot route to etonitazene which is why these cheap, poor derivatives keep turning up. No real medicinal chemists are involved in the design and development of novel opioids... because they tend to want a decent income... so people try to do without; and we see the results of THAT false economy.

ibb.co

1

Image 1 hosted in ImgBB
ibb.co ibb.co

Above is the MOST potent analogue, ant it's x240 morphine. All these dumb figures saying it's thousands of times more potent then M are based on animal models.... the same kind of model that stated BDPC was x10000 M.

There is a long German paper on this compound. It's on the Eunoia disc.
 

BTW above link confirms potency of etotonitazene and my figure of x60 M seems accurate.

But their ARE very potent opioids. Most certainly their are several compounds 3 steps from commercially available compounds >x510 and upto x3600 WITH a lot of supporting data.

What I THINK is happening is the money-men are deciding what they want. They no longer employ medicinal chemists who can work out the most profitable compounds.

But I've listed many compounds that so far have not been spotted and I know their are more in papers and patents.
 
Fertile said:
Above is the MOST potent analogue, ant it's x240 morphine.
Click to expand...

that i didnt know. halogens on the phenyl 4 dont seem to do the trick. t always thought that alkoxy was best for the class of benzimidazoles. never stumbled upon an alkyl substituent.
 
The ethoxy is space-filling. That the isopropyl is 1/2 as potent gives in insight into the biosteric minimum of the receptor. Think about it, that -O-CH(CH3)2 can equally exist in 2 equally minimum energy states. So can the ethyl so if one could find a way to fix which conformation the ethoxy adopts, one could double that potency....
 
Actually, a THF ring might work thus:

ibb.co

1

Image 1 hosted in ImgBB
ibb.co ibb.co

Now the above will be more rigid but one might have to move dihydrofuran and their would have to be enough space in receptor BUT it forces that terminal -CH3 into a specific space. Maybe furan (being slightly smaller) would alter activity but it's never been tried.

WO-2007091950-A1

Comounds with the THF are known but they also have CB1 affinity. So maybe the parent has some CB1 affinity? The amide side-chain provides NOP affinity so although it's analgesia is 4 times that of the parent (if chiral), you might get more out of it.

But If the lead compound is x60 and THAT is worth making, the derivative with the carboxamide should be worth it. After all, all one has to do is have a -C≡N by heating in solution of water, tert-butyl alcohol and LiOH (why LiOH is preferred isn't something I bothered to look up. Also there is work using Cu catalysts that are chiral but their are simple ways to resolve and dehydrate unwanted isomer.

I suspect it's not going to cost twice as much... but just as fentanyl is being made by 'cooks', the simple route to this class leads me to suspect that again, it's 'cooks' who earn about £250/day. I'm guessing they are staying ahead of the law.

But as I said, their is a compound legal everywhere but UK that is x3600 M in 3 steps - and that's a figure derived from tests on multiple species so it's a robust figure. Much easer to make 1Kg of this rather than 45Kg of fentanyl. Oh, and it's very euphoric. So if fentanyl wholesales for $4150.... well, work it out... x45.
 
I've often wondered why RC vendors don't fluorinate O-DMT. USRE37355E1 examples 2 & 5 (the trans pair) have a combined analgesic dose of 1.46 mg/kg. In the same test tramadol had an ananlgesic dose of 13.60 mg/kg. OK so tramadol is a mixture of 2 isomers,

That's about x3 more potent than O-DMT. Also I PRESUME O-DMT will be controlled eventually and so this would be the obvious replacement. OK the fluorination requires some nasty reagents (they use DAST but in the last 20 years, much better alternatives have been introduces.

As F&B puts it 'driving a locomotive through the laws on drug control'.

So when this happens, is it going to be O-DMFT or some other daft acronym? We need a brand manager to figure out brand names ;-)
 
izo said:
interesting observation. dont know any opioid expert you could consult.
Click to expand...

The expert to consult is Professor Helmut Schmidhammer at the University of Insbruck. I have almost no German and very limited Dutch so it has proven difficult to contact him.
 
The 14-methoxy metopon guy, yes. He is still there. I checked a few weeks ago.
 
Then write me what you want to ask I’ll add something and you can send it. Ok? Tried contacting the am guy some weeks ago but no reply, but he’s really old by now.
 
You must log in or register to reply here.
Top