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Azabicyclane opioids analgesics

paracelsius

paracelsius

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Mar 11, 2020
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does anybody have any info on this compound and related series ?
220px-Anazocine_structure.svg.png

they're a series of meperidine-type analogs bridged at 3-5 by a propane. wiki doesn't say much. from what I get, this compound is about similar analgesic potency as morphine (rats, mice and rhesus). Now, if you add a hydroxy meta on the phenyl ring, the potency jacks up to 500 times morphine. change the stereochemistry at the benzylic carbon (from beta shown->alfa conformer so the phenyl is axial), the potency shoots up whooping 1200x morphine. Replace the N-methyl by phenethyl (beta conformer), the potency goes to the roof about 2500x morphine. I would appreciate your input, in case anybody has come across some old (or not old) literature on those..thx
edit: wiki entry says it was developed in US that's not correct; it was developed in Japan not the US. The harvard study they reference is a confirmation study of the Jpn study. it even does cite the japanese papers.. kind of disingenious to claim is was developed in the US (credit where credit is due I've been taught)
 
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I seem to recall an Italian team working on azabicyclane opiates. An exhaustive search of the papers using Reaxys showed that simplification of structure to a cis dimethyl piperizine. produced a less active, but still active series and replacing the N-methyl with p-nitro cinnamyl group was an order of magnitude stronger than M. Buccinazine (AP-273) is the parent compound and azaprocin a result of research into AP-237. The compound you mention must be a bitch to make but a cis 2,6-dimethyl piperizine is simple.

Actually, the references on the Wiki page CC azaprocin has clearly been copied from the Eunoia disc directly. Not many Wiki pages have 18 references to related but active medicines.
 
Good eyes!, I missed that: yeah changing the piperidine to a piperazine would give azaprocin-like and related diazabicyclopiperazines or their methyl piperazines derivatives like AP-237. iirc, the highest mu agonist activity the italians got with azaporicn OP was like 25xmorphine (with the 4-nitrocinnamyl azaprocin). With the azapiperidines I am talking about though (azabicyclane aka anazocine), the increase was enormous (I mean like 500xmorphine just by adding a OH. At first, I was suspicious since companies sometimes claimed whatever. Until I saw the harvard paper confirming that. (actually up to a remarkable 2500x!! Quite amazing considering how simple those compounds are.

No, actually, unlike the diazapiperazines (which are bitch to synthesize), these are very easy, actually straightforward in only 2 steps from commercial azabicycloketone (arylgrignard to ketone->arylcarbinol->MeOH+sulfuric acid et voila! thats how the japanase made it). 1 extra step for the meta-hydroxy but you get the idea I am sure). (I'll post refs later if anybody interested).. Thanks for your input..
 
I think all the complex ring systems make for interesting drugs. It makes me think of how close to some opioids the cocaine structure is. Toss the nitrogen around and substitute a bit and you could probably find something. I believe some phenyltropanes have opioid affinity.
 
The Straub tail reaction is not a good estimate of potency in human beings. I've seen dozens of compounds that were supposed to be >x10000 M and while potent, they turned out to be around x500 M when tasted. Believing potency data from a paper is a really fast way to end up dead. Potency is no guide to euphoria either. Long ago I came to the conclusion that anything too strong to eyeball needs to be in caps or soluble tablets and patient-packed so it cannot be adulterated. Anyone who has tried capping or patient packing, even WITH right kit will KNOW what a pain it is.
There are some excellent, novel opioids x2-x10 M that no customs agent would spot... they aren't even on the EUnoia Disc.
 
Different type of teil reaction, that is. I do get a Straub reaction of sorts when pretty ladies walk by though.

Anyway (once we can collectively get back on topic), I think I posted the tropane analogue of theis compound. Is the methoxy analogue of demerol/prodine an active opioid of any sort?

2eF2FRT.png
 
Ah - I tried the p-Chloro analogue of the above. It had stimulant properties but wasn't too water-soluble so painful to snort.

There IS a slightly more complex but achiral (or, rather, the precursor is chiral by nature) coke analogue that is water soluble and a local anesthetic. The latter may suggest hERG proliferation. Pseudotropine + p-Nitro benzoic anhydride --->nitrophane. MOST people will not be able to tell if it's pure coke or the simplified analogue. NOW I must point out that nitrophane has not been tested enough for me to state that it is safe. It's just interesting that almost no studies used the p-nitro unless I missed em.
 
sekios structure makes me nervous. Not the structure itself but the serious potential to fuck up synthesis with a benzylic leaving group elimination gives you what?

answers on a postcard to the Parkinsons Trust.
 
clubcard said:
Ah - I tried the p-Chloro analogue of the above. It had stimulant properties but wasn't too water-soluble so painful to snort.

There IS a slightly more complex but achiral (or, rather, the precursor is chiral by nature) coke analogue that is water soluble and a local anesthetic. The latter may suggest hERG proliferation. Pseudotropine + p-Nitro benzoic anhydride --->nitrophane. MOST people will not be able to tell if it's pure coke or the simplified analogue. NOW I must point out that nitrophane has not been tested enough for me to state that it is safe. It's just interesting that almost no studies used the p-nitro unless I missed em.
Click to expand...
p nitro tropacocaine, not a great idea from a safety point of view.
if the p fluoro is any guide to go by, p-nitro it is a more potent sodium channel blocker and a less potent monamine transport inhibitor than cocaine itself which in turn means it is more likely to cause sudden people becoming dead type issues than cocaine.
 
vecktor said:
p nitro tropacocaine, not a great idea from a safety point of view.
if the p fluoro is any guide to go by, p-nitro it is a more potent sodium channel blocker and a less potent monamine transport inhibitor than cocaine itself which in turn means it is more likely to cause sudden people becoming dead type issues than cocaine.
Click to expand...


No, the p-F is not a great guide. The p-F is much less potent than cocaine as a CNS and was rather more of a local anesthetic i.e. too much hERG proliferation (so sodium & potassium channels of the heart) that made it cardiotoxic. The p-nitro analogue as I mentioned, is almost exactly like coke. Same anesthetic dose, same stimulant dose. The problem is that aromatic nitro groups are obviously something that medicinal chemists will worry away at. If ester hydrolysis is the predominant metabolic pathway then maybe it's OK BUT unless you can rule out P450 splice variants producing a different metabolic pathway that will only turn up when a large cohort is involved, who know? Who wants to find out a year later that it's harming people? Evidently the people cutting cocaine with worming-tablets are not similarly held back by their ethics.

I should also add that smoking the freebase could be dreadfully toxic. Another unknown. So nitrophane was just another page of the also-rans.
 
So what is the Kv11.1 affinity? and how does it move it, that curve that gives you a guide to hERG liability, otherwise you are hand waving. Sodium channel related toxicity in cocaine is not hERG, which is a pretty specific mechanism, hypertension other arrhythmia and other things are significant downstream effects from channel blocking.

taking just hERG to summarize:
you don't know the affinity and activity of p-F
you don't know the affinity and activity of p-Nitro
so anything you say regarding hERG is pure speculation.
These numbers are easy and cheap to get. The gold standard of course is patch clamp but the luminescence assays are pretty accurate and cheap.

I think you are making a bunch of wild guesses and that someone might think you have more real knowledge on the matter than you actually do, and choose to do something really stupid on that basis.

There is nothing wrong with nitro, but the usual issue is metabolic activation and hepatic toxicity with nitro groups and med chem has been burnt enough to be wary of nitro.
 
Is that what you think. Well, that's me told. People can make their own minds up, I'm sure.
 
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