Anazocine Opioids analgesic AND SDNRI

[paracelsius]

So I took a close look at the OP compound aka anazocine discussed some time ago. Quite possibly one of the most euphoric OP (AND stim!) known to man. Or at least one of the most addictive. Afaik, it is one of the very very few compounds that morph-trained macaque monkeys would gladly prefer it to IV morph (from that japanese study mentioned in previous thread). I mean by day 30, the monkeys were self-IVing it at a whopping rate of 300 times a day (20mg/kg dose)..300x/day!! basically non-stop dosing themselves 24/7! Which means huge tolerance develop quickly, but surprising they didn't OD (up to 150mg/kg IV in OP-naive animals, they did fine according to the authors.. expect I could only imagine the euphoria at that huge dose .. more like IV-ing cocaine AND heroin at the SAME time..why I say that? read-on

I been trying to see why is this compound so addictive? well it turns out, as I read that old japanese paper, the original synth actually gives a 30:70 ratio of the cis and trans isomer (from the reaction of the corresponding bicyclic ketone with phenyl-grignard).

Now, if you look closely, the trans isomer superimposes neatly (>80% ) to the cocaine analog Troparil, a DNRI, and the cis isomer superimposes to the mu-opioid agonist ketobemidone or to demerol. So in other words, the trans isomer is (very likely imo) a DNRI (as potent as cocaine?) and the cis a mu-Opioid agonist (~4x more potent than morph found by those studies). Quick swisstarget prediction predicts Serotonin Norepinephrine Dopamine Transporters, Sigma and mu-Opioid as the top 5 most likely targets (which is what I suspect). In other words it is a mu-opioid agonist and (most likely) a SDNRI as well.

So basically I think what those guys were dealing with was the ultimate speed-ball (the 30:70 mixture of cis-trans isomers) with the trans isomer acting as a stim as potent as cocaine (more I would say, probably 5-10x more, from troparil-type cocaine analogs SAR) and the cis isomer acting as a mu-OP agonist (~4x morph) within similar dosing range.

I mean, the ED50s for SDNRI and mu-opioid agonism are probably within same range so the dose will activate both SNDRI and mu-OP at the same time!! that's an opinion tho (data for SDNRI not done afaik only that of mu-OP, analgesia and locomotor in rats and macaques). This probably explains why the monkeys didn't OD, SNDRI activity counteracting OP respiratory depression, making it "safer" than pure OPs like fent, but way much more euphoric and addictive!? .. Now, I don't know about the SNDRI of that chem (that hasnt been done afaik, just comparing the trans compound with troparil on paper)..

But I would bet my last shirt, trans-Anazocine is a potent, cocaine-like Serotonin-Dopamine-Norepinephrine Reuptake Inhibitor and cis-Anazocine a potent mu_opioid agonist and the reason monkeys prefer it to IV-morph is probably due to that: they were basically speed-balling non-stop on 20mg/kg of the drug .. have a good'day y'all BLighters....

 

[clubcard]

There exist a number of recognised Mu/DRI ligands. Nortilidine is the most widely appreciated but in fact there are a number of agents. I believe Land De Traume had a report on nortilidine and the DRI and Mu effects were keenly noted. There are a few related compounds known to be similarly or more active.

 

[polymath]

And then someone with a high opioid tolerance but none for stimulants takes a dose and gets a heart attack.

 

[clubcard]

And then someone with a high opioid tolerance but none for stimulants takes a dose and gets a heart attack.

I do not think tolerance to heart attacks occurs with stimulants. If the compound the OP noted has hERG activity, tolerance certainly does not occur.

 

[Nagelfar]

I do not think tolerance to heart attacks occurs with stimulants. If the compound the OP noted has hERG activity, tolerance certainly does not occur.

cc, do you mean to say, with stimulants, that one does not become more tolerant of effects otherwise liable to cause heart attack; so there is no lessening the potential one might occur?

That severity of the heart attack itself is not diminished (considering the factor of some measure of opioid dependence)?

Otherwise are you meaning sensitization, or that tolerance to opioids doesn't raise risk of heart attack in stimulant naïve individuals, or that stimulants are not prone to heart attacks generally?

The post in question that your responding to I think is what left me a bit bemused; wasn't polymath inferring that if an opioid dependant individual were to take the dose their habit required for the desired opioid effect, that a racemic might likely be considered a stimulant overdose?

My apologies if I made too much of this;
The severity of the soliticted inquiry I hope finds itself somewhat abated by my telling you that your opinion here is one I hold regarded as among the most well respected.

 

[clubcard]

Yes - both acute & chronic stimulant abuse is hazardous. Of course chronic use can lead to chronic toxicity but I do not think tolerance reduces risk. Obviously stimulants that interact with hERG have a dose/toxicity curve that certainly is NOT altered by tolerance.

It's worth noting that the Mu/DRI ligands were initially seen as central analgesics that didn't cause sedation. It turned out that the abuse potential was dramatically increased. The Land Der Träume reports on nortilidine were overwhelming. There are actually quite a few Mu/DRI ligands bearing the cyclopentane moiety.

 

[clubcard]

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ibb.co

Out of interest, this is the reverse-ester of nortilidine. It can be produced in 2 steps from 1-phenylcyclopropene. Of course, this is quite well known. Something with a better LogP and higher affinity would be more useful (this stuff is only around M in potency and too costly to make). Such compounds have been researched but the work is not well known. The cyclopentane is the motif to look for.

 

[vecktor]

Out of interest, this is the reverse-ester of nortilidine. It can be produced in 2 steps from 1-phenylcyclopropene. Of course, this is quite well known. Something with a better LogP and higher affinity would be more useful (this stuff is only around M in potency and too costly to make). Such compounds have been researched but the work is not well known. The cyclopentane is the motif to look for.

^ out of interest Nortilidine is a cyclohexane 6 carbon ring not a cyclopentane 5 carbon ring.

 

[clubcard]

^ out of interest Nortilidine is a cyclohexane 6 carbon ring not a cyclopentane 5 carbon ring.

True - but the cyclopentane analogs are more active. The research most certainly went down the cyclopentane path.

 

[paracelsius]

There exist a number of recognised Mu/DRI ligands. Nortilidine is the most widely appreciated but in fact there are a number of agents. I believe Land De Traume had a report on nortilidine and the DRI and Mu effects were keenly noted. There are a few related compounds known to be similarly or more active.

You are absolutely right. The classic example is the mu-agonist Meperidine (Demerol) which incidently is also a potent DNRI. It actually fully substitutes for cocaine. The issue is really whether ED50 for MOR and DAT are within the same range or hugely different. iirc Meperidine ED50 @ DAT is ~10x higher than that @ MOR. So that at analgesic doses, you'd probably not have any stimulation. At stimulants doses, you'd probably opioid OD! Vice-versa, if the compound ED50 @ mu is higher, then you'd have pure stimulation and less opioid activity. I don't know about Nortilidine or the cyclopentyl homologs but I suspect the ED50s for mu & DRI are widely different!

Izenwasser, Sari; Amy Hauck Newman; Brian M. Cox; Jonathan L. Katz (January–February 1996). "The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter". European Journal of Pharmacology. 297 (1–2): 9–17. doi:10.1016/0014-2999(95)00696-6. PMID 8851160

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..Something with a better LogP and higher affinity would be more useful...

What is wrong with the logP? To me it seems about perfect (+/- 2.5 predicted depending on software). That is as optimum as it gets for a CNS compound. Unless you want to increase half-life or something by increasing logP.

Only problem I see tho: is the free base stable? wouldn't the free base lead to an aziridine, (the secondary amine attacking the benzylic carbon with propionate leaving). especially in that configuration (amino and propionate in trans). But i guess that won't happen with the salt.

 

[clubcard]

For a centrally acting drug, a LogP close to but below 5 is ideal. Overall solubility is, of course, important but as long as it conforms to the RO5 then it will be active (or at least pass into the brain but could be actively transported out, I guess) but the sheer COST of the compound I noted means that it isn't commercially viable. Now, I have seen some opioids in which the phenyl is replaced with a 2,6-xylyl moiety. Not only does it increase LogP but it also makes the rings more rigid (non-rotatable). That said, I am not certain if the relative aromatic-N: position/rotation would be idealized. I mean, in the case of isopethidine, making the rings non-rotatable improves matters but it would require a good training set to test a new compound... and I do not have such a thing. I am presuming that 20 compounds are needed for a decent training set.

Because something works in theory doesn't make it practical. Something cheap and synthetically simple is a lot more attractive... or something much more potent.

 

[paracelsius]

For a centrally acting drug, a LogP close to but below 5 is ideal...

Not quite. Way too lipophilic. Yeah, sure the more lipophilic the compound the more likely it can cross BBB by passive transport, tho it might end-up p-glycoprotein substrate!

For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1: Medicinal Chemical Properties of Successful Central Nervous Drugs ...https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201314/

But it really depends what one is trying to achieve. Problem with highly lipophilic CNS compounds: poor water solubility/ bioavailabilty, slow onset (at least orally) and long half-life. + Tend to accumulate in body fat and slowly released from there. So if the idea is for a slow-onset, long-acting then yeah higher logP (~5) would be best bet. Like the piperazines DAT inhibitors that were developed as cocaine “replacement therapy” ala Methadone for opioids. The idea being that a slow-onset/long-acting compound may have less abuse potential and still substitute for coke. So in that case logP~5 would be ideal

Another example is THC (logP~6). It sure hits fast when smoked but it takes forever when eaten, isnt it? with the unfortunate consequence of kids “OD-ing” (it is legal where I live) thinking they haven’t eaten enough brownies!!! compare that to meth near perfect LogP~2.

 

[clubcard]

I DID mention overall solubility. LogP is RELATIVE solubility in H2O:n-octanol rather than overall. As for methadone, well try smoking the freebase - it hits faster than IVing the stuff i.e. within 10 seconds. Duration is generally mediated by metabolism of a species. The rate of metabolism is related to it's volume of distribution AND it's affinity.

 

[sekio]

As for methadone, well try smoking the freebase

this does not seem a smart idea to me

 

[Neithman]

this does not seem a smart idea to me

why? Smoking impure heroin base off foil is tho?

 

[polymath]

why? Smoking impure heroin base off foil is tho?

Intravenous methadone causes QT interval prolongation and arrhythmias more often than oral dosing, and if this is because of the faster onset then smoking is likely to be even more dangerous in that sense.