• 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

Most pleasurable opioid based on pharmacology?

sekio said:
I was just about to reply the very same thing. On paper acetylketobemidone sounds like a yummy compound.
Click to expand...

The phenol can be swapped for a carboxamide -C(O)NH2 for equal potency, longer duration. I have rad that it is more potent but the pKa & LogP values might not be ideal....
 
Wouldn't something like oxymorphazone or chloroxymorphamine be more pleasurable? i.e. irreversable binding? long duration?
 
In Naked Lunch, William S. Burroughs would fantasize about his dream opioid, "dihydro-oxy-heroin" (that, and Jism. Lots and lots of Jism.)

Presumably he imagined it as a hybrid between his favorites, oxycodone (he was shooting up a German brand, "Eukodal") and heroin (duh!).

Now, I could see two potential structures for this: If we define "heroin" as having two acetyl groups, it would have to be 3,14-diacetyloxymorphone.
4%2C5%CE%B1-epoxy-3%2C14-diacetoxy-17-methylmorphinan-6-one.png


Another possibility would be 14-monoacetyl-oxycodone:
4%2C5%CE%B1-epoxy-3-methoxy-14-acetoxy-17-methylmorphinan-6-one.png


Whereas alkylation/acylation at the 3-hydroxy-group generally impairs an opioid's activity (but may improve bioavailability), substituting an ether or ester at the 14-position has been demonstrated to greatly increase it to a level comparable to some of the Bentley compounds or fentanyl analogues. Not sure how quickly that acetyl group would get cleaved off, though.
 
It could also be the enol ether of oxycodone or oxymorphone, with two or three acetate groups present, viz. thebacon (hydrocodone enol acetate).
rnQSZmT.png


Dihydroheroin itself and 6-monoacetyldihydromorphine are quite nice, actually... long t1/2 and almost as potent as "normal" H
 
Presumably dipropionyl morphine and its dihydro analog are also worth looking into, I think any of the lower esters are good.

The esters are certainly better drugs pharmacokinetically speaking, better BA and they are effectively prodrugs for the central delivery of their dealkylated opiate meabolites.
 
sekio said:
Presumably dipropionyl morphine and its dihydro analog are also worth looking into, I think any of the lower esters are good.

The esters are certainly better drugs pharmacokinetically speaking, better BA and they are effectively prodrugs for the central delivery of their dealkylated opiate meabolites.
Click to expand...
That's what I had figured. Limpet Chicken said it was his favorite opioid and he's tried many!
 
sekio said:
Presumably dipropionyl morphine and its dihydro analog are also worth looking into, I think any of the lower esters are good.

The esters are certainly better drugs pharmacokinetically speaking, better BA and they are effectively prodrugs for the central delivery of their dealkylated opiate meabolites.
Click to expand...

The 6 ester is cleaved more readily when the 7-8 double-bond is reduced. Think of it as an allyl alcohol. I think the propionoxy is also more readily cleaved BUT maybe the 2 cancel each other out (how unscientific is THAT posit!). Dibenzoylmorphine was trialled in the UK and was indistinguishable from diamorphine. I think the Dinicotinylmorphine is the best one to try out. The dinicotinate of nalorpine is a partial agonist shown to produce analgesia in opioid na?ve patients. Pyridin-3-ylmethanediyl dipyridine-3-carboxylate anyone? Take a stroll through the patents on 8-Carboxamidocyclazocine (touted as treatment of cocaine misuse syndrome). First, replacing a phenol with a carboxamide increases duration (but introduces a chiral centre because the -C(O)NH2 cannot freely rotate). The researcher then turned to high-throughput screening and found some quite complex derivatives of the carboxamide that produced sub-nM affinity. One of Janssen's books on opioids is devoted to the benzomorphans and while phenazocine was the only one he got to market, he spotted features that places them in the super-agonist catagory and I don't mean N moieties. Swapping the 13-(R)-methyl for a 13-(S)-methoxy (like adding a 14 methyl ether to oxymorphone) increased potency by a factor of x216 (almost exactly the same as oxymorphone to 14-methoxymorphone). If the phenanthracine QSAR can be applied, swapping the N-methyl for an N-2-ethylaryl doesn't work. It appears to be one or the other. Certainly 14- hydroxy<acetoxy<propionoxy<propeonoxy<cinnamyloxy works but somehow, leaving the N-methyl and just making the methyl ether is..... more elegant. Forming the hydrogen carbonate and reducing? Who knows, Of course, most larger ethers don't work as well. I've sweat blood trying to find a stylish way of introducing the ether;

Rearrangement of allyl to ketone has been a pressing question in commercial production. The original German patent using palladium black had a much lower yield than specified because it was calculated from BRSM (by remaining start material). For a long time double-bond reduction & oxidation OR oxidation & 1,4-reduction (tributyltin hydride does an admirable job but isn't cheap). As recently as 2003-2008 a Pfizer researcher claimed yields of 97% initially using Ru(0), Rh(0), Pd(0) and Pt(0) species with a O=PX3 (X = halide) catalyst but it had the look of bench-top scale only. Inert atmosphere, strict stoichiometry & Suprapure™ reagents and solvents. I believe that the chemical engineers ran into serious solvent management/catalyst recovery issues and the idea stalled. Codeine -> oxycodone -> oxymorphone -> 3,14-diacetyl (or does ketone zwittrion make the 6-7-alkenol?). Still, lots to play with.

But back on topic, the μ/NMDA stand out in the euphoria stakes. Adding a first generation antihistamine (cyclizine, tripelennamine, diphenhydramine) are added to give a bigger 'flash'If someone mixed said antihistamine to norisotilidine (μ/NMDA/DRI) then I think it would be VERY impressive. I know Diconal, termed 'strawberry milkshakes' because the colour of the pills cannot be totally removed, mixed with methylphenidate for a bigger rush (bigger than dipipanone + cyclizine FFS!) but if ONLY we could 'breed in' antihistamine activity ;-) No, I truly believe INT will have a very large and very long-lasting (10 minute or more) rushing, never mind the buzz! Only morphine potency so the scum buying carfentanil wouldn't even consider it....
 
Hm. I couldn't say if dipropionylmorphine or dihydromorphine would be the better of the two.

I have never tried dihydromorphine, although I have tried 6-monoacetyldihydromorphine (one dose, albeit a fairly strong one, 300mg, IV, and given there was only a single dose available, it was mixed with memantine in the same shot)

And have tried dipropionylmorphine, and enjoy it immensely. Although I've never mixed it up as a 'memantine speedball', on its own or with stimulants it does provide a phenomenal rush and is also extremely long lived. The rush is not highly prolonged, but in the case of the 6-monoacetyldihydromorphine/memantine (300mg of the former, unweighed but used as received, plus a couple of hundred mg memantine), that one knocked me sideways into...well I'm not quite sure where, but I sure as hell know WHAT. A rush that lasted approximately 3/4 hour, intense enough for the entire duration bar the very tail-off of the initial IV rush, then a fairly prolonged and intense nodding high. I'd say of the two, bearing in mind the fact that there was only a single dose of the 6-AcO-DHM available for testing and that it was mixed with memantine, the 6-AcO-DHM was definitely most impressive.

I am currently seeking a memantine source, and once I manage to find one I shall most certainly try a mixed IV of prope and memantine.
 
Update-there should be trials in the offing, this time including dipropionylmorphine, diacetylmorphine, 6-monoacetyldihydromorphine with, and without memantine included in the shot, and 6-monopropionyldihydromorphine, as well as dihydromorphine straight, after first formation of the 6-acetyl ester and alkaline lysis of the ester. Again, with and without memantine, get some standardized trials done.

(thanks, you know who you are)
 
Bayer tried any number of (mixed) diesters as well as monoesterification. In fact, 3-propionoxy-6-acetoxymorphine was the worlds first CsA (designer drug).. or the 3-acetoxy-6-propionoxy, I forget. Measuring the diester of 1 compound with the bare hydroxyl moieties on another is a little bit like apples and oranges. Most aficionados in NZ who have tried morphine hydrochloride and dihydromorphine hydrochloride prefer the former. Why bother with swapping salts? Onset of HCl is noticeably faster than the sulphate or phosphate. Diamorphine comes as the HCl in dry-amps specifically for it's rapid onset.

Of course, removing that 7-8 double-bond means deprotection doesn't need to use pyridine HCl or a boron halide (one stinks, one kills you - both bad ideas). From the patents, 22% HBr with H3BO3 catalyst (a pinch of borax is favourite), circa 87% yield. I know that Russians burned the pharmacists down in this town buying boxes and boxes of dihydrocodeine+paracetamol. In situ HI from your choice of brewing sanitizer and a pinch of purple powder gets way more desomorphine & deoxymorphine-D than plain codeine.

But back on topic. I know piritamide has fans. In The Netherlands it's nickname is 'dip' (rhymes with 'pipe') and they always want drugs that are [P] in most of Europe but [POM] in their homeland. It has a hit along the lines of the other μ/NMDA agents. That seems to be the magic and none of them are particularly potent. I mean, I cannot fathom the continued circus around fentanyl. It's not very euphoric and the euphoria->OD window is small. A scout around of what is commercially available, what the cost will be and how much the stuff sells for means the right μ/NMDA agent with, let's say x4-x8 morphine potency with a long high allowing BID means it could easily be worth double of whatever the stuff they cut into the paracetamol/caffeine mix and have the cheek to call heroin. I've known of people getting a stretch just for having p/c or piracetam in bulk (the latter preferred frr-north USA & East European excipient).

There are some very, very well researched agents that have a VAST TI as in the LD50 of the parent & the x60 derivative ate the same! THAT is the kind of window anyone who cared about the punters would go for. Opiate dependence is a social issue, not a criminal issue. I'm all for giving juice/bup or even M wet amps to people. Saves money in terms of acquisitive crime reduction and families not being torn apart when someone dies. Methadone is a good analgesic, has an amazing flash when the freebase is smoked and costs pennies. It might look strange on the face of it but someone who realizes that a new opiate that suddenly ends 911 calls because people will not die if they are given 10 times the dose they expect. 2-3mg I guess so 20-30 won't kill them. Nothing says 'death sentence or life if you're lucky' more than selling fentanyl or the 1001 flavours emerging to beat the law. I see someone has bypassed the class law by introducing a halide onto the piperidine ring. Too strong is not good. Making illegal drugs is bad. Selling desperate people poison is bad. a Well chosen, novel μ/NMDA dual-agent with decent but reasonable (you can eyeball a dose) would seem like a no-brainer. It isn't even close to anything controlled so why smuggle it in? Just have it sent with the IUPAC on it! Let them check. Even the Eunoia Disc doesn't have them all and boy were opioids THE research field for a good 30 years........


Sorry. I'm all for informed choice but a random chemical in a random cut is uninformed. Sublingual pills (like the original Temgesic) cook up as clean as H jacks so suck, snort, swallow, shoot or shove it up your shitter - it will be the same every time. I remember Kgs of H wil gold-leaf brand logos on them. Rice Brand & Tiger Brand were the big ones where I'm from.
 
The most recreational and euphoric opioids are morphine and it's esters. Morphine sulfate, morphine diacetate (heroin, diamorphine), morphine dinicotinate (nicomorphine), morphine dipropanoate (dipropionylmorphine), morphine dibenzoate (dibenzoylmorphine), dihydromorphine (Paramorphan), desomorphine, diacetyldihydromorphine, etc.

After the above, I'd place hydromorphone, oxymorphone, heterocodeine, hydromorphinol, pentamorphone, and pethitidine next.
 
Sometimes heroin has a bunch of other good drugs mixed in with it, such as papaverine.
 
Sometimes I wondered if 'good' heroine contains things like noscapine (supposedly a NMDA antagonist not unlike DXM, never sampled it though and might be much weaker, maybe still strong enough in combination to make a difference) as there are just so many myths out there about otherworldish euphoria, less tolerance/dependence (possibly cause 'addicts' tend to wait until withdrawal before aqcuiring new stuff, yet might this also cause worsening if indeed the withdrawal / rebound itself causes its worsening) etc.. but theres of course other explainations.

Morphine has a very different character depending on ROA and speed of onset. Never IV'd and morph's the only opioid of that Ive used plenty, but guess diamorph will be even more pronounced here. I get it only while tolerance is low, but you can catch an excitatory (rare) experience, that keeps you up all night. Other an inhibitory (common) one, with the urge to sleep. As dose increases, you can get mixed experiences (nodding, probably) but as said, with tolerance it becomes a pure sedative to me. Indeed there are inhibitory and excitatory opioid effects in neurology with the excitatory ones showing rapid tolerance.

Just that indeed mu/NMDA is like the king of euphoria. As you get more euphoria with less opioid, when done correct it's pretty safe too, and you want to stop? Titrate the opioid out and use the disso as long as you get symptoms. Strange so few people are actually using this. Maybe methadone made the docs think that it doesn't work but it's just a bad example..
 
Last edited:
sekio said:
From what I remember, studies seem to indicate that morphine and heroin differ only in potency; that is to say heroin is mainly a high-BA prodrug for morphine.[ref] Esterases convert heroin in the blood to 6-MAM and morphine quite rapidly so the major difference is in potency alone.

That's for purified diamorphine, the stuff sold on the streets is not necessarily "heroin" at all.

It's also worth noting that there are also the delta, kappa, and nociceptin receptors and activity as a histamine releaser to consider. Possibly also mu-dopamine receptor dimers to consider too.
Click to expand...
That AND the histamine release are the only differences. Diamorphine Is only superior cause it has a faster/better Rush AND less histamine release. Apart from that they're the same.
 
Interesting, somehow I thought of the histamine being part of or even responsible for the excitatory effects which, for me, greatly add to the experience as the actual euphoria, not 'just' absence of negative emotions, correlates almost 1:1 with the itch on morphine. O-DSMT, as far as I remember, though didn't come with any itch and was maybe 1/2 as stimulating and 1/2 as sedative, making a similar experience.
 
Hodor said:
In Naked Lunch, William S. Burroughs would fantasize about his dream opioid, "dihydro-oxy-heroin" (that, and Jism. Lots and lots of Jism.)
Presumably he imagined it as a hybrid between his favorites, oxycodone (he was shooting up a German brand, "Eukodal") and heroin (duh!).
Click to expand...

Well, some (maybe?) interesting sociocultural facts:

When invented, Oxycodon was released under the brand name Eukodal in Europe (in the year 1919), and for decades it was mostly known as Eukodal, while the substance name "Oxycodon" was nearly unknown.

In older Gerrman Dictionaries there's even a word for the addiction to Oxycodon: Eukodalismus (similiar to "Alkoholismus" =alcoholism) and the user itself was called an Eukodalist. The habit was very common within clinic doctors at that time. In the time between both world wars, there was a very large consumption of psychoactive substances in Germany, the people wanted to forget the horrors of the war. Cocaine, Heroin, Eukodal and others were legal and could be bought in every pharmacy.

For opiat users these were really Golden Twenties!!
 
kokaino said:
The most recreational and euphoric opioids are morphine and it's esters. Morphine sulfate, morphine diacetate (heroin, diamorphine), morphine dinicotinate (nicomorphine), morphine dipropanoate (dipropionylmorphine), morphine dibenzoate (dibenzoylmorphine), dihydromorphine (Paramorphan), desomorphine, diacetyldihydromorphine, etc.

After the above, I'd place hydromorphone, oxymorphone, heterocodeine, hydromorphinol, pentamorphone, and pethitidine next.
Click to expand...

ive had a lot of morphine and i never felt any euphoria on this crap.
i must say tianeptine is the most euphoric opioid in the world! i mean, out of all those obscure ones you guys are mentioning. whats the point if nobody can get a hold of them? tianeptine is still LEGAL and the most potent opioid i ever had in my life. this coming from a guy doing oxies, morphine, shooting heroin etc. and i thought ill never meet my match until i did tianeptine. BUT because its potent opioid activity only lasts 30 mins and its more of a stimulant, glutaminergic, it turns off some people using it. especially heroin addicts i dont think they get it. but its actually more potent than heroin ORAL DOSE. heroin doesnt even work orally! i never shot tianeptine, but comparing it to shooting heroin, i felt the exact same high, high dose, as shooting heroin. only for 30 mins though. the asshole glutaminergic stimulative effect takes over and lasts for 6 hours at time and you need benzos to take off the edge. but yeah, i still can claim its the most potent underrated opioid out there thats ACCESSIBLE.
 
You must log in or register to reply here.
Top