AP-236, other p[iperazine opioids

[Limpet_Chicken]

Of late, I have been reading a little about a class of structurally novel opioidergics, represented by a 1-acyl-4-cinnamylpiperazine backbone, the most potent of the class without any further modifications appears to be 1-butyryl-4-cinnamylpiperazine.

Reading up on it, it seems in this study, comparing the drug with aminopyrin, that the 1-propionamide at least, behaved like an opioid agonist rather than an antiinflammatory such as an NSAID or crAPAP, but there appear to be very widely conflicting results about tolerance.

This drug, AP-237 is the 1-(n)-butyryl amide and it seems has a fairly long history of use in china. Unfortunately I ended up running into what looked like it was probably some paywall filth, although I couldn't be sure since I do not speak or read chinese.

There are quite a few journal references which try to suggest that it has relatively little propensity towards developing physical tolerance and habituation, yet the wikipedia states that it does so quickly.

More to folllow on here.

 

[cdin]

i too am extremely interested in this class. I would love to find a compound that blends a bit of the effects of both - or even one that just has pleasant dissociative effects. I can no longer take classical dissos due to bladder malfunction. or a straight opioid effect. all three are welcome but yeah, w/piperazines in general being such diesel substances, I think there's probably a lot more interesting ones in the pharmacological family.

 

[LucidSDreamr]

seems like one of the easiest opiates i've ever seen to make

 

[DotChem]

Very interesting compounds indeed: the cinnamylpiperazine are actually derived from azaprocin an aza tropane mu opiod developed in italy. a bunch of analogs were made in italy in 80's as tentatively "non-narcotic opioid" which is kind of silly! they're actually pure mu agonists with the 4-Nitrocinnamyl azaprocin about 25x morphine. Replacing the the ethyl CH2CH2 of azaprocin or removing it altogether gave still very potent mu agonists like AP-237 that used in China but withdrawn due to reinforcing effect. Strange there were not developed further (like for RC market) as they seem straightforward to prepare
I think some of the cinnamyl piperazines were available as RCs in the Netherlands some time back with some good reviews actually

 

[Limpet_Chicken]

We are going to find out pretty damn soon. Will give a report as soon as the synth is done. All is at hand.

Will try the N-cinnamyl-N-propionamide as well, as well as the cinnamyl-benzoyl amide. IIRC the propionamide is slightly more potent than the butyryl amide, although the acetamide, from a recently read paper looks almost inert.

Dissociative effects? these compounds are NMDA antagonists as well? Well damn, it was only xmas a month ago. Looks like its coming three times this year if that proves to be the case

Will report on this ASAP. If its anything like the synthesis of DM-235, the AMPAkine, then total work is likely less than an hour. Do be warned however that reported dosages at higher levels are NOT to be repeated by default, I'm highly tolerant to opioidergics.


Although mind you, my synth of DM-235 used the acid chloride for doing both amines, using a mono-salt of the piperazine, acylating, deprotection via isolation of the freebase then drying and acylating with the other acyl halide, so a little faster than using an anhydride. Still, probably not very much in it. Was randomly browsing interesting wikipedia articles when this opioid happened to be noticed. I'd reckon anyone that could make GHB, or chlormethiazole/bromethiazole in terms of skill could have this done in no time. Surprised it hasn't appeared on the streets in fact its THAT simple.

Cdin-what about lefetamine and derivatives, such as diphenidine and methoxphenidine? The bladder issues are specific to the arylcyclohexylamine family are they not?

Despite the price of n-butyric anhydride, methinks dibutyrylmorphine shall have to be tried as well, its reportedly more potent than morphine, but less so than diamorphine on a mg for mg basis. No idea about subjective effects in comparison. But a few drops of n-butyric anhydride to prepare a few hundred mg of dibutyrylmorphine can be spared, cook off the remaining anhydride (for a few hundred mg of product, sod stoichiometry, a pinch of NaOAc to assist the rxn, why not. 3,6-dipropionyl seems to be the sweet spot for potency and quality. But just for a taste test, since morphine is not the limiting reagent, the anhydride is, for some reason n-butyric anhydride (sigma) is ridiculously expensive. But a drop or two can certainly be spared.

The 1-butyryl-4-cinnamylpiperazine is likely to be tried tonight, with any luck, using cinnamyl chloride, the mono-amide freebase could even act as its own HCl-scrubbing amine to neatly form the HCl salt of the tert.amine.

MOR-selective, highly reinforcing opioids in an hours work sounds pretty good to me in fact. No need to watch for dependency much, since I've been stuck with a longstanding injury, that surgery only made worse, that horse has already bolted, and if worse comes to worse, I have oxy(codone) and morphine (or dibutyryl/dipropionylmorphine to fall back upon. Worse thing is, I end up withdrawing for 1-2 days every damn week, because my drs are too stingy for the most part to give me enough to last those last few hours. Problem solved, hopefully. And if nothing else, never tried dibutyrylmorphine before, so might as well at least once. Less potent than prope dope from what I read on wikipedia, but still, a new one to taste. Why the hell not

But, regarding these cinnamylacylpiperazines....dissociative effects? seriously? I'm liking the sound of this ever more so the more I read.

Withdrawn in china for reinforcement reasons...that sounds pretty good, especially considering they use dihydroetorphine over there (!) like we use methadone or bupe.

 

[Limpet_Chicken]

Update-alkylation procedure has been done.

Awaiting a minor hotplate fix, old man is going to take a look at that, since he's the electronics geek, then the freebase N-cinnamylpiperazine will be isolated and acylated. Several hours in anhydrous acetone suspension w/a little bicarbonate to scrub any HCl, a little EtOH to get the rxn kicking, and hopefully, that part should be done.

Leaving behind a slight cinnamon-like smell. I HATE cinnamon usually, but in traces, its actually not too bad. The butyric anhydride however...that is going to be less pleasant of a task. Isn't butyric acid the main culprit for the awful smell of vomit?
I may save a portion of the N-cinnamylpiperazine however, and prepare the propionamide also. The latter is reportedly slightly more potent than the butyramide, although its true, the smell of either propionic acid or its chloride are both pretty vile.

Either way, bioassay coming up as soon as that hotplate gets fixed. Should prove interesting.

Now, about the mention of NMDA antagonism, can anyone provide references for this? or reports from any bioassays first-hand, from when these turned up on the RC scene or otherwise. I'd be most interested in dissociative opioids. Doesn't diphenidine have some properties pertaining to both, as an analog of lefetamine? lefetamine sounds like an absolute blast, opioid, dissociative and stimulant in one package. What more could one want (unless you count a classic autistic nymphomaniac girl for who'm any perversion goes. But sadly thats not something I can pull out of a flask)

 

[Limpet_Chicken]

I'm going to have to do more testing with this.

Not quite sure what to make of it. Is it possible this series of compounds are partial MOR agonists of fairly high efficacy? because I can't say its wonderful. Will have a crack at the propionamide, since I saved half of the intermediate alkylpiperazine (roughly)

Going to give it half an hour or so, and if no improvement, probably knock myself out w/ chlormethiazole&nitrazepam.
I was already going into withdrawal from morphine at the time a test dose was taken, and felt like shit. Now, I feel..less like shit but still like shit. Which I wouldn't expect from a full agonist.

That said, it could be because I have to take GABAergics for seizure prophylaxis, and there are no abrupt signs of precipitated withdrawal. Last dose of morphine taken earlier this morning. For now, going to redose the chlormethiazole which won't unduly sedate me so I can better gauge what is responsible for which effects.

And being followed around by the smell of butyric acid is..less than pleasant

 

[Limpet_Chicken]

It seems I was right. Being late with the GABAergics. I feel, no euphoria, but no or minimal withdrawal either.

The rest of the intermediate piperazine (N-cinnamylpiperazine) will be saved for production of the propionamide. Making the butyramide isn't a particularly pleasant process. I can still smell the leftover butyric acid from the anhydride. Unfortunately it was a fair bit more expensive so I opted for the anhydride rather than n-butyryl chloride. Smells like the after effects of a frat party and several barrels of gut-rot tequila.

Some warm glow as a result of taking the product (plugged, since there were still traces of butyric acid present. Not enough to irritate skin or tongue, (PH tested FIRST before that test) but the smell of butyric acid is not pleasant. Like vomit, and there was no way I could have gotten that down without doing sufficient workup to eradicate the last traces of it without gagging. And the only gelcaps of any kind I have, happen to be the one-piece kind that pharmaceutical chlormethiazole is dispensed in, and as such would have been no use.

 

[ralf2]

There is an old report on the effects of AP-237 here on bluelight:

http://www.bluelight.org/vb/threads/273287-piperazine-opioids?p=11946869&viewfull=1#post11946869

 

[Limpet_Chicken]

I don't recommend any opioid user that is physically dependent upon a full agonist try these.

Further research is in order.

But, having administered a dose of the propionamide homolog to this, again, something just isn't right.
Onset of repetitive yawning and lachrymation within minutes of administration.

Alright maybe there is something to this (I just woke up after being asleep nearly all day, despite not having taken other than chlormethiazole, 192mg. Which on its own certainly wouldn't put me to sleep unless I was heavily sedated.

I will re-examine the butyramide, although with reservations.

Although suddenly waking up to find 9 tenths of the day just disappeared to the stench of butyric acid...I'm not sure if its that thats making my eyes water, or the propionamide wore off. Although I don't feel withdrawal kind of shite, but what I think are the beginnings of it.

It will be more interesting to test these from a known stable dose of morphine, or dipropionylmorphine, to see if any of these are partial agonists.

D2 antagonism might explain it. Opioids are about the only thing that will stop me feeling like total shit in the case of the former, I'm really oversensitive to D2 antagonists.

 

[Nagelfar]

a bunch of analogs were made in italy in 80's as tentatively "non-narcotic opioid" which is kind of silly!

Yep, like the U.S. claim in '94 about oxycodone being non-addictive when it was approved for prescription, Bayer pharmaceutrical saying that heroin was a cure to morphine addiction, and loperamide being inactive regardless of dose because of affinity to P-glycoprotein.

 

[adder]

D2 antagonism might explain it. Opioids are about the only thing that will stop me feeling like total shit in the case of the former, I'm really oversensitive to D2 antagonists.

You mean these might be D2 antagonists as well? That's not unlikely they have some affinity at dopamine receptors given the structural similarity to butyrophenones and some atypical antipsychotics based on piperazine or piperidine. If so many analogues of azaprocin were made, maybe some study included screening for affinity at dopamine or serotonin receptors, I don't have time to check this now though.

 

[Limpet_Chicken]

I don't mind taking one for the team, in order to tease out what isn't right. But freebase N-cinnamylpiperazine is already at hand. All that remains is recrystallization, forming the amide, freebasing the amine half again, washing and rextyl'n. Although as I said, the propionamide is meant to be slightly more potent in any case as an opioidergic. I hadn't taken a dose of morphia for a day or so beforehand, and it DID appear to relieve it at first, (the butyramide this refers to, I tested relatively little of the propionamide. But again, I was in withdrawal, I felt utterly shitty to begin with and was in no hurry to do more than purification and PH adjustment. Now, I can do this with a full agonist opioid in my system and in no such state of misery, and as such, devote such time as needed to get to the bottom of this. Although, the butyramide will be likely the last of the series I do, since the other amides can be made rapidly, using the acyl halides. The butyramide must be made using the anhydride. And having that, I am NOT willing to pay sigma's prices for the acid halide. And the reason for it being likely the last one, is that stench of butyric acid. I awoke at 5pm today give or take, and that stench STILL hung around. Stank like a dive bar after a gutrot spirit party by gangbangers with stomach problems the day after, the barkeep and or janitors all having been murdered and the vomit left to moulder. Butyric acid just got added to the list of things I find truly vile. Not pyridine-bad, isycyanide-bad, acrolein or mercaptan-bad, and nowhere near overheated chlormethiazole-evil (don't....thermal cracking of that drug is the pits. I'm surprised my waste disposal didn't throw up. but certainly up there with some of the nastier stenches I've had the experience of. I feel as enthusiastic doing anything that involves it as I do dipping my arse in HNO3 (believe it or not, in the 1700s, this used to be used as a treatment for piles. I suppose it must have worked, in that it would stop sitting down causing pain from pressure upon somebody's piles. But only since you wouldn't DO it for the next few weeks)

 

[cdin]

thanks for the note on the lefetemine derivitives, I hadn't kept up enough with new research. I'll wait and see how trip reports and long term experiences stack up before I dive in... too old for that first out of the gate shit anymore.

 

[Limpet_Chicken]

Well, the R&D is certainly going to be made public as soon as thorough work is done.

However just for the time being, the propionamide rather than the butyramide is going to be made the primary target, whilst the butyramide is now assigned second priority. The propionamide is, reportedly as I believe I stated, slightly more potent than is the 1-butyryl-4-cinnamylpiperazine, although not by a great deal.

Primary reason for this, the slight increase in potency, going from mouse figures in terms of EC:50 and LD-50 values being slightly lower for the propionamide vs N-butyryl-N-cinnamylpiperazine, not however dramatically, is not being particularly used to use of carboxylic acid anhydrides rather than the equivalent acyl halides for amidations, not sure if in the case of the anhydride, that an asymmetrical 'hemi-freebase' for want of a better term (by this is meant, for example, piperazine-4-hydrogen phosphate, one of the amine nitrogens being present as a salt, the other as the free base secondary amine. So from now on, for conveniences sake, this type of compound will be referred to henceforth as a hemi-salt or hemi-base. It'll do as far as nomenclature goes. And the numbering is rather irrelevant really, considering that in a symmetrical diamine base such as piperazine, the two amino nitrogens are equivalent if no further substitution is present upon either the piperazine carbons or nitrogens bar one of the amines being a salt, the other the base.)

As it is, never liked acid anhydrides much, especially for amidations, given they complicate workup with an equimolar quantity of the carboxylic acid and the amide. And butyric acid in particular is vile. Propionic acid isn't nice, but butyric acid has this nasty way of following one about like the bastard child of a homing pigeon and a skunk with a gastrointestinal tumor. Stinks akin to concentrated eau-de-vomit and would follow one cheerfully to the gates of hell

The acyl and acid halides on the other hand, are far more atom-efficient, giving off HCl rather than refined essence of yesterday's breakfast come back to haunt one. And faster, too. And ideally if the alkylation is the first step rather than acylation, the cinnamylpiperazine would serve itself to absorb the released HCl, simplifying workup.
One hopes


Never tried lefetamine itself, but have tried diphenidine and methoxphenidine, and found both of them to be very enjoyable. Not sure if these possess opioidergic activity directly as MOR agonists (as opposed to modulation of opioid receptors via NMDAr antagonism), in the case of diphenidine, the solubility in H2O however is piss poor, needing heat to induce dissolution, however methoxphenidine is much more soluble in H2O, shorter acting though, presumably in both these cases the reason is the increased polarity of MXP compared to diphenidine itself courtesy of the methyl ether.) Methoxphenidine seems significantly more potent however than does diphenidine, (it should be noted the route of administration was intravenously for both drugs usually, or occasionally plugged. Never tried either of them orally, may have tried MXP insufflated but never diphenidine that I can remember.)

Given this thread (wrongly titled btw, I accidentally made a typo and could a mod please change the title to AP-237 for me?)
brought up mention of possible dissociative effects, with some of this family of opioids, is this thought to be KOR agonism (I seem to recall some of them being compared to pentazocine as well as morphia) or NMDA antagonism?