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    Phenylpiperidine Opioids - how low can you go? 
    #1
    https://imgur.com/MpSH05v

    So, we have a chiral carboxamide as a bioisostere of a phenolic group, an ethylsulfonyl group as bioisostere of ethyl ketone and shock - an N-2-furanylbenzyl as bioisostere of the common or garden N-ethylaryl. I have an unknown. Substitution of the piperidine ring is supposed to be verboten for ketobemidones BUT picenadol (LY-97435) suggests the reason why such substitution failed was simply because like many phenolic opioids, they can be agonists and/or antagonists. I dare not believe that swapping the methyl for an allyl would engender a serious increase in potency BUT it does raise the issue of what has been left untested. When the side-chain bares no oxygen, the chain-length is important. A methyl is an antagonist, an ethyl is a partial agonist (see meptazinol) while (S)-picenadol is an agonist.

    It has nothing special to make it a clandestine target but as a series including the 2,5-dimethyl as well as various 3-n-alkyls and N-benzylaryl groups (thiophene, thiazole, oxazole & isoazole for example) WOULD be of tremendous value as a training set. MANY 5 & 6 membered aromatic rings have been placed onto the anilidopiperidine scaffold and many times more on the dual mu/delta ligands that have gone nowhere but the example I give is one of around x20 morphine based on the (English) patents.

    Going even simpler, dimethylaminopivalophenone overlays 3,3-dimethylpethidine BUT the position of the O is the same as one of the Os in allylprodine so what activity would people predict for dimethylamino-3-allyl-3-methyl-heptephenone (suppose it's about as accurate as the original!). If the allyl works I predict that replacing the N-methyl for an N-allyl in U-47700 will have pronounced effects.
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    #2
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    That almost looks like carfentanil.

    Are carboxamides really chiral under those conditions though? Biphenyl-3-carboxamide is achiral so shouldn't it be achiral on the (sterically uncrowded) pethidine skeleton?
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    #3
    It is chiral according to Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute. There is a raft of patents and papers on the benzomorphan scaffold but the amide is chiral... That is a VERY interesting piece of information. I do not believe this is widely known. I'm purely interested in the ways to improve acute safety. I am sickened by the endless tide of phenylpropanamide opioids wreaking havoc all over the world. In the 1950s it was noted that substitution of the N-methyl of levorphanol (Levo-Dromoral) with a 2-arylethyl had an ED50 some 1/60th of the parent, the LD50 was HIGHER (by MW specifically) and a chiral β-hydroxy reduces that to 1/240 (by MW again) so already the TI is 2 orders of magnitude larger. It is possible to improve delta & keppa-3 affinity to reduced the ED50 by another couple of orders of magnitude and the LD50 is once again increased by the same ratio.

    So you can produce something in the range of carfentanil with an LD50 in the range of codeine. It isn't that it needs a long, complex and/or expensive synthetic pathway. It's ignorance, laziness and to produce a crack-like (ab)use pattern. If something has a T1/2 of 4-6 hours BID, not even TID is all that is needed to stop people being sick, you don't sell many units. When I see reports on fentanyl caps at $2 each, the low price many units model is in place. The Russians call tropicamide '8 monther' for a reason and I presume fentanyl has similar names.

    I cannot quite understand the mindset of someone who is happy to grow rich on the misery of others. Something much, much better than diamorphine would surely not come to the attention of law enforcement is nobody is dying or carrying out desperate criminal acts to constantly feed the needle. Sublingual tablets like the very old UK diamorphine 'jacks' and with appropriate livery, you could reduce the harm hugely. The bar is quite low - alcohol and nicotine are deadly. We can and should be doing better for people.

    For joint mu/kappa-3 look at the etonitazene derivatives with a carboxamide on the methylene spacer. for joint mu/delta look at allylprodine, cinnamyloxycodeinone & etorphone. Run a training set through CHARMM (with selective k-3, selective delta & selective mu). I used a set of 96 so the thing chugged away for a good couple of weeks but who knew and alkene is an important moiety? I'm dubious of modern in-silico models but old fashioned 3D QSAR works if you train them correctly. I don't think I'm smarter than anyone else but I always try to be informed. Yes, I am often wrong, but it is the answer that is important, not how the answer was arrived at (as long as it's legal and moral).
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    #4
    Esters don't substitute for ketones. Sulfonates & phosphine oxides do. Reducing the ketone moiety of ketobemidone and esterification of that would be interesting.
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    #5
    The Proof Is In The Pudding.
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    #6
    Quote Originally Posted by Dresden View Post
    The Proof Is In The Pudding.
    Well the ethanesulfonate works. The phenol-->carboxamine i'm prepared to bet will work but the N-(2-furyl)benzyl may have unselective kappa activity. They were 15x more potent in animal models but who knows if it's nice. Adding a 3-methyl works as long as you can resolve the trans-pair. One is an agonist, the other an antagonist (which is why early research discounted it) so (S,S) 3-methyl ketobemidone is an order of magnitude more potent.
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    #7
    clubcard,

    I love your posts, but can you draw more pictures?
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    #8
    https://en.wikipedia.org/wiki/File:Picenadol.svg

    Note (3R,4R) isomer is the agonist, while (3S,4S) is antagonist.

    The reason why substitution of the piperidine ring of ketobemidone didn't seem to work was because phenol-bearing opioids can be antagonists. From the extant data we can infer that 1-[(3R,4S)-4-(3-hydroxyphenyl)-1,3-dimethylpiperidin-4-yl]propan-1-one will be around a magnitude more potent than it's parent, ketobemidone. Phenol bearing phenylpiperidines do not follow the N-substitution patterns of the non-phenolic ones. A british patent listed 1-[1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)piperidin-4-yl]propan-1-one ketobemidone derivative as some x15 more potent than the parent. N-moieties with a nitrogen 2 methylenes from the piperidine N means we can infer it's the lone-pair that is critical. Put it all together and 1-[(3R,4S)-1-(furan-2-ylmethyl)-4-(3-hydroxyphenyl)-3-methylpiperidin-4-yl]propan-1-one is going to have 2 extra moieties that improve affinity.

    Not possible to say if it will be euphoric (kappa 1/2 agonism an issue) but from extensive studies and my own work using CHARMM, I would expect it to be some 100-150 x the parent. Of course, CsA laws apply so swapping ketone for an ethylsulfonyl (tested on both phenolic & non-phenolic phenylpiperidines and is equipotent so 3-[(3S,4S)-4-(ethylsulfonyl)-1-(furan-2-ylmethyl)-3-methylpiperidin-4-yl]phenol shoult work and swapping phenol for carboxamide leads to the compound I drew.
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    #9
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    Looks like if fentanyl and demerol had a baby. But ignore me, I'm not qualified to make such statements.
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    #10
    Well it isn't phenolic... it will metabolize to a phenolic compound and non-phenolic bemidones aren't that active BUT and alpha methyl will harden the stuff. Swap benzene for 2-furan and dump ring-substitution. I reckon it would be active. Not safe, not good, not something I would try but active.... but something that kills you is active as well :-D
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    #11
    https://ibb.co/ddCgOL

    There you go. The ethanesulfonyl & n-propylsulfonyl were equipotent in animals but the latter was more toxic. It's something of academic interest because the nature of unlicensed opioid vendors means that the maximum profit for the minimum risk far outweighs any concept of safety to the end user. Maybe that's obvious but I would have thought people NOT dying and NOT entertaining criminal acts to fund the eternal escape from rattling would have kept them off radar. That's the killer - not knowing what is actually being sold.

    https://ibb.co/coA2f0

    And the above is some x240 M in potency. I suspect that the analogue baring an N-methyl and 14-methoxy moiety would be similarly potent but I don't know of a practical way to make the methyl ether of such a tertiary hydroxyl. As it stands the synthesis isn't tremendously complex (as long as you identify & source the appropriate precursor) being 3 steps but I suspect still beyond the Chinese suppliers for whom I have an engrained distrust in having seen a few thousand NMR/GC-MS sets.

    https://ibb.co/c6J500

    So... I contacted Derek P. Reynolds and although he is named as inventor in the patent, he openly stated that all he did was build dreiding models with bond angles calculated using pencil and paper. You will note it overlays cypenamine which is ,I presume, why tilidine has a small but loyal following in Germany. You may also spot that it overlays isopethidine and I would suggest that it's 50-50 that placing an o-Me onto the aromatic ring will increase potency since (Lipinski's rule of five) it will make the aromatic<->cycloaliphatic ring non-rotatable.
    Last edited by S.J.P.; 03-11-2018 at 00:48.
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    #12
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    Quote Originally Posted by clubcard View Post


    So, we have a chiral carboxamide as a bioisostere of a phenolic group...
    Quote Originally Posted by clubcard View Post
    It is chiral according to Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute. There is a raft of patents and papers on the benzomorphan scaffold but the amide is chiral... That is a VERY interesting piece of information. I do not believe this is widely known.
    The structure as drawn does not make sense. The amide nitrogen is shown pointing up, suggesting that a pair of diastereomers are present when the molecule would otherwise be achiral. This is impossible behaviour for a carboxamide group.
    Last edited by S.J.P.; 06-11-2018 at 07:22. Reason: Somehow missed that the molecule is achiral.
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    #13
    Axial chirality or atropisomerism is commonly found in substituted biaryls in which the rotation around aryl-aryl bond is restricted, but it's also observed for substituted benzamides when there is enough steric bulk present on the amide and the aryl ring to prevent free rotation around the >NC(O)-Aryl bond. In this particular case there's nothing in the structure that would hint at restricted rotation around the >NC(O)-Aryl bond though (compare with examples here), but who knows, maybe it's the hydrogen bond(s) between the sulfone and the amide that make it chiral. Still, I'd say such chirality could be observed for this compound under specific conditions (in solid state or fairly apolar solvent) but it doesn't look like the barrier to rotation is so high that it'd be tightly locked, e.g. if you put it in a polar solvent with Lewis basic properties like DMF or DMSO, or water, I doubt you'd observe axial chirality there. I could be wrong though, I haven't seen the paper on this.
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    #14
    Quote Originally Posted by S.J.P. View Post
    The structure as drawn does not make sense. The one stereocentre in the molecule is undefined, yet the amide nitrogen is shown pointing up, suggesting that a pair of diastereomers - not enantiomers - are present. This is impossible behaviour for a carboxamide group.

    Now, it may be that the amide is not flat relative to the benzene ring; this is a reasonable assumption, as even benzamide does not have a flat crystal structure. Perhaps the nitrogen acts as a hydrogen bond donor to one of the sulfone oxygens:



    However, the fact that the amide skews in a given direction based on the configuration of the molecule's stereocentre does not make the amide itself chiral.
    Fell free to forward this to Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute.
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    #15
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    EDIT: never mind, see Novaveritas's post.
    Last edited by S.J.P.; 06-11-2018 at 07:23.
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    #16
    Quote Originally Posted by S.J.P. View Post
    The difference between this situation and axial chirality is that axial chirality can occur independently of a stereocentre in the molecule. In this case, the fact that the amide might be geared via hydrogen bonding with the sulfone does not make it chiral. If the opposite configuration of the quaternary centre is present, this should induce the opposite configuration of the amide. The amide itself cannot be "inverted" (and I put this in quotes because the amide isn't actually tetrahedral, just rotating a certain way) independently of the quaternary centre.



    I'd be quite interested to see the original claim, in fact. Perhaps there is more to the explanation?
    I think there is a reading comprehension thing where clubcard has gotten things ass backward, the patents claim varios benzomorphinans which are most certainly chiral, but their chirality has sweet FA to do with the amide somehow being chiral, The molecule above is achiral it has free rotation and an axis of symmetry. There is not usually any rotation locking on a meta position even in biaryls.

    off topic
    Q in QSAR does not stand for questionable structure activity relationship. Q is for quantitative.
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    #17
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    I always thought aromatic amides were planar and therefore achiral. See benzamide:


    Even something like DEET is achiral:


    I thought this was partly due to the low inversion barrier of nitrogen, unless locked into a ring system like quinuclidine. And amides also want to be planar because they have some resonance forms with a N-C pi bond.

    You do get axial chirality in e.g. polysubstituted biaryls like BINAP though (and phosphines can actually be stereocenters because they have much higher inversion barriers):
    Last edited by sekio; 06-11-2018 at 04:15.
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    #18
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    Quote Originally Posted by novaveritas View Post
    I think there is a reading comprehension thing where clubcard has gotten things ass backward, the patents claim varios benzomorphinans which are most certainly chiral, but their chirality has sweet FA to do with the amide somehow being chiral, The molecule above is achiral it has free rotation and an axis of symmetry.
    Yikes, I had it ass-backwards too, the amide drawn with a wedge must have thrown me off because I missed the plane of symmetry. Good catch.

    Quote Originally Posted by sekio View Post
    I always thought aromatic amides were planar and therefore achiral. See benzamide:


    Even something like DEET is achiral:
    Amides, aromatic or otherwise, are planar. As can be seen from the crystal structure of benzamide, however, aromatic amides are not necessarily coplanar with the aromatic ring they are attached to. In any case, amides are certainly not tetrahedral and I can't think of a situation where an amide unilaterally induces chirality in a molecule.
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    #19
    I have given reference - there are dozens of papers and patents covering it.... I didn't just make it up! Daniel Lednicer's thesis was on helicine and used the same notation so maybe i'm just lost in the past. Worth noting that -P(O)H- also substitutes for ketone. I know IC-26 is the only one noted but the same German team also made and tested them.
    Last edited by clubcard; 06-11-2018 at 19:41.
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    Quote Originally Posted by clubcard View Post
    I have given reference - there are dozens of papers and patents covering it.... I didn't just make it up! Daniel Lednicer's thesis was on helicine and used the same notation so maybe i'm just lost in the past.
    Helicenes frequently have axial chirality so it wouldn't be unreasonable to see an aromatic amide with indicated chirality in that case, although it would make more sense with the wedge/dash drawn between the aromatic C and the carbonyl C, as opposed to between the carbonyl C and the N.
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    #21
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    Is there any way to put that furanyl thing in the place of n-methyl in morphine? I think an n-phenethyl substituted version was 14x more active than morphine, so much the same SAR as with the piperidines.
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    #22
    Quote Originally Posted by polymath View Post
    Is there any way to put that furanyl thing in the place of n-methyl in morphine? I think an n-phenethyl substituted version was 14x more active than morphine, so much the same SAR as with the piperidines.
    YES. N-[2-(furan-2-yl)ethane]-normorphine is x45 M. A 2S hydroxyl (spot overlay with fentanyl) is some 96x M.

    https://www.unodc.org/unodc/en/data-...4_page007.html gives a useful QSAR.
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    #23
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    Probably more healthy than krokodil...
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    #24
    Quote Originally Posted by polymath View Post
    Probably more healthy than krokodil...
    YES.

    I just cannot fathom why it's just F abalogues that are turning up. If U-47700 was sufficiently profitable then something with the reputation of being the most euphoric opioid on the planet would appear attractive. The methylfuryl moiety may confir too much sigma activity but the 2 N-ethylaniline analogue of ketobemidone hinted at in Opiates (Lenz et al) and detailed on the Eunoia Disc shows that in stage 1a trials at least, parenteral administration suggested that it was some x6.5 more potent and had the same set of side-effects. Given that 25mg of ketobemidone = 60mg of morphine (parenteral) suggests 15-16x M. Of course, it's synthesis is lower yielding but once again.... just what profit margins do these clandestine chemists want? Is 10000% still too small? I don't know.

    The book by Lenz can be downloaded free by anyone. It only convers around 50% of the opioids on the Eunoia disc but it's still a MASSIVE storehouse of data.
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    #25
    'Healthier than krokodil'

    And the award for understatement of the fucking year goes to..........

    Although as far as I'm aware, desomorphine-D itself, isn't responsible for the horrific effects of that noxious shite, its all the corrosive byproducts and the poor workup of synth FAR too harsh for phenanthrene opioids (here I'm referring to the Nagai reduction, it's just too damn harsh.)

    Been meaning to give it a go when I'm back on my feet properly (had a recent operation on one leg, still not up for too much walking), did get as far as alpha-chloromorphide, but that proved too interesting to test in its own right, so never got around to trying catalytic reduction with Pd/C in iPA to reduce the intermediate cleanly.
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