Levorphanol, Opiate and Dissociative.

[MedicinalUser247]

Levorphanol is both an Opiate and Dissociative. Its known to be a powerful Opiate with a potency 6 to 8 more times as potent as Morphine, but I've never really heard of anyone being prescribed it. I just think it's interesting because of it's effects. Which are both Analgesic and Dissociative. What are your thoughts on this ?

 

[AlsoTapered]

No, it's just an opioid analgesic with some NMDA antagonist activity. Ketobemidone & methadone are also opioids with NMDA antagonist activity but NOBODY has ever suggested that they are dissociatives.

IF you are making a statement that seems TOTALLY unknown to the world of medicinal chemistry, a reference.... indeed several references would be MUCH appreciated.

Since 2mg is the usual dose of levorphanol (maximum 8mg/day) and it's NMDA antagonist activity is slightly lower than ketamine - you would be LONG dead before any dissociation was noted.... although I suppose death IS dissociating....

BTW read the rules for posting in this sub-thread please. Baseless speculation is specifically mentioned.

 

[MedicinalUser247]

I got my information off Wikipedia. Mabey I just didn't read through it right. So, I could be wrong.

 

[AlsoTapered]

We use journal articles here. So here some for you to hotlink to:

The Journal of Pain vol. 13 iss. 4 pp.S77 The in-vitro analgesic pharmacology of levorphanol: effect on NMDA, opioid and monoaminergic systems DOI: 10.1016/j.jpain.2012.01.320 a a	N. Babul; A. Rehni; H. Kao; Y. Chang		2012 April		English
	European Journal of Pain Supplements vol. 5 iss. 1 pp.115 F143 CHARACTERIZATION OF THE IN-VITRO ANALGESIC PHARMACOLOGY OF LEVORPHANOL: EFFECT ON NMDA, OPIOID AND MONOAMINERGIC SYSTEMS DOI: 10.1016/s1754-3207(11)70392-3 a a	N. Babul; A.K. Rehni; H.D. Kao; Y.S. Chang		2011 September

https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=ce9f5bdc4f8559372b64f17ac02482c738e4e436

https://journals.sagepub.com/doi/full/10.4137/PCRT.S13489

https://pdfs.semanticscholar.org/631a/6981d24fa3f9176753113bd4b2c213c5867f.pdf

Levorphanol

Levorphanol | C17H23NO | CID 5359272 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

FYI this would be considered a MINIMUM amount of reference acceptable when one is asserting something novel. Just like submitting a dissertation you WILL be asked to expand on some areas and answer HARD questions (with reference).

Although SciHub is down, all of the articles are still available to those who ask,

So if I make a statement and someone asks a question, I can provide those references, I ONLY used Wiki because it was closest to hand. I would NEVER use it as a reference although it IS worth exploring the references that were used to build said page.

So while others argue that they 'invent' (although never make, test, or explain their rationale), they do so because what might take 2 minutes to post here takes me on average 6 days of work researching. Because it's not guessing - I'm simply adding 1 block to a pyramid of knowledge (which I first read, checked and understood)

BUT the most OBVIOUS place to begin is https://erowid.org/archive/rhodium/chemistry/levorphanol.html

 

[AlsoTapered]

A good question might be - how would one modify levorphanol to increase it's duration of action? To do that you need to know the metabolism. Well I will tell you, N-demethylation (and norlevorphanol is considered active in it's own right) and by ester formation at the phenolic 3 position.... so one would need to explore what else could go at 3.

The answer is again, that place I say we do not accept references from BUT use references IN:

8-Carboxamidocyclazocine - Wikipedia

en.wikipedia.org

Swapping the phenol for a carboxamide slightly reduced potency but read the references and the T1/2 increases by a factor of 8.

Now that would see a huge accumulation of the nor metabolite and frankly an analgesic that lasts for days is generally a bad plan, but it's EXACTLY the sort of question someone might ask.. so I would HAVE all of those references ready, a rationale of why it WOULD would similarly in levorphanol and even a sketch of the synthesis (which is actually just 2 steps).

But here we post facts or ask questions. EVERYONE is welcome to ask questions... but 'I might have read it wrong' I am afraid, isn't likely to win friends or influence people.

In short - it's a LOT of work. If you come up with 1 novel thing a week you will be doing well. I have 34 years of experience to rest on so maybe I don't recall WHICH paper, but I know it was in a paper I read and I will spend days (if needed) finding that paper.

I don't mean to be hard on you, but we have 1 muppet who if I had any control wouldn't be able to post here. As it is they have their own thread and nobody else even bothers to look. I advise you to avoid them like the plague. They WANT to convince someone, ANYONE that they are a genius.

I most certainly am not, but I do work hard. Their is no substitute for that.

 

[negrogesic]

Levorphanol is both an Opiate and Dissociative. Its known to be a powerful Opiate with a potency 6 to 8 more times as potent as Morphine, but I've never really heard of anyone being prescribed it. I just think it's interesting because of it's effects. Which are both Analgesic and Dissociative. What are your thoughts on this ?

In the above table, you'll see that levorphanol has a far greater affinity for the MOR than it does for the NMDAR, so it's unlikely to have noticeably dissociative effects at ordinary doses. The doses required to produce notable dissociative/classical psychotomimetic effects would be overshadowed by the MOR agonism (if one is even able to remain conscious).

 

[AlsoTapered]

The above would be and indeed IS considered an acceptable reference.

Interesting that methadone is only one sixteenth as potent as an opiate as levorphanol but is almost as active at the NMDA.

Also interesting that it's more potent than dextromethorphan. Now long ago a Dutch friend would buy DXM and deprotect it to DXO which he considered a much better NMDA antagonist. It would APPEAR that NMDA activity is unconnected to the chirality of the compound.

Now I've seen DXM been shilled on the internet as an NMDA antagonist but I don't believe I've ever seen DXO ever marketed as such.

If you want an NMDA antagonist, MK-801 (dizpcipine) is the most potent known. Now as a few BLers know, it was I that developed diphenidine, ephenidine and isophenidine. MK-801 is structurally very similar to ephenidine. The major difference being that MK-801 is rigid. I'm fairly certain that a p-Me on the A ring would increase dopamine activity and act as a sacrificial moiety.

After all, MK-801 is just too potent and too dangerous. Deaths attributed to sub-mg doses make it a VERY dangerous compound but what a surprise, some vendors were offering it.

 

[sekio]

I that developed diphenidine, ephenidine and isophenidine.

Well, thank you for making my life a lot more fun during that little stint. Were you also responsible for methoxphenidine? (I'd have put the MeO on the meta position personally)

> Now I've seen DXM been shilled on the internet as an NMDA antagonist but I don't believe I've ever seen DXO ever marketed as such.
Isn't there considerable evidence that DXM's activity is actually via metabolism to DXO via CYP2D6? Hence the whole "white grapefruit juice makes your trip harder" rumour.
Certainly the affinities show DXM is more of a SNRI than a dissociative.

 

[AlsoTapered]

Well, thank you for making my life a lot more fun during that little stint. Were you also responsible for methoxphenidine? (I'd have put the MeO on the meta position personally)

NO, and it killed quite a few people. the second-rate chemical company we used couldn't get a halide onto the ortho of the B ring which is why they added a methoxy. There have been quite a lot of deaths associated with methoxyphenidine because their is NO data on 1,2-diphenylethylamine NMDA antagonists with B-ring substitution. Oh, and those were not people who would self-test...

I came up with isophenidine as an improvement to diphenidine... but the lousy lab had already bought 250l of piperidine (smuggled into the UK as N-methyl pyrrolidine) and used every excuse in the book as to why they could NOT make isophenidine. First the BP of the amine was the excuse ... so I provided an RT route. Then the yield was 'really low' so I gave reference to 96% yield and finally 'isopropylamine is a watched precusor' so I asked for reference. Then they got worried and dropped the price on methoxyphenidine.

Of course the boss; the man who put in cash has no understanding of chemistry whatsoever. But when the lab said methoxyphenidine was CHEAPER than isophenidine, I had no way to counter that. I REALLY hope they made a loss on it.

I think one of the isomers binds to something which produces toxicity:

https://www.sciencedirect.com/science/article/abs/pii/S2352007822002876

The crappy lab ONLY resolved isomers if I expressly asked them to. After all, if ALL the good stuff is produced by 1 isomer, as long as a chiral synthesis costs < double... you make the optically pure product, obviously.

If I sound angry it's because I am. Do you know the first sample they sent, they had used pyrrolidine and not piperidine.... and THEN went on to attempt to argue in spite of the GC-MS & NMR being available! Shady people.

BTW I cannot obtain the full version of that paper. If anyone can I would be eternally grateful.

 

[sekio]

Available for a short time only: the paper.

It's literally just the text available as the abstract.

I can't believe I wasted 25 bucks on that. Ho hum.

(Why are they using dibenzoyl tartaric acid? seems like an expensive and kind of silly chiral ligand but what do I know)

 

[polymath]

Some compounds with a structure somewhere between the PCP type and bromadol type molecules could be both an opioid and NMDA antagonist with similar affinities to both receptors, but the problem is that an opioid usually needs to be a tertiary amine for significant mu affinity while dissociatives need to be secondary amines. I'm not sure why someone would design that kind of a substance unless it is to be an actual pharmaceutical that gives more analgesia compared to respiratory depression and possibly causes physical dependence more slowly than usual. A recreational drug user can just dose some dissociative and some opioid at the same time, but for an actual medication it's better if both effects have same duration (as happens when both are caused by same substance).

 

[AlsoTapered]

Some compounds with a structure somewhere between the PCP type and bromadol type molecules could be both an opioid and NMDA antagonist with similar affinities to both receptors, but the problem is that an opioid usually needs to be a tertiary amine for significant mu affinity while dissociatives need to be secondary amines. I'm not sure why someone would design that kind of a substance unless it is to be an actual pharmaceutical that gives more analgesia compared to respiratory depression and possibly causes physical dependence more slowly than usual. A recreational drug user can just dose some dissociative and some opioid at the same time, but for an actual medication it's better if both effects have same duration (as happens when both are caused by same substance).

Well suggest the key moieties required in an NMDA antagonist, suggest the key moieties of an opioid analgesic and suggest how the two could be reconciled within the BDPC scaffold.

A few opioids have some NMDA activity, but none seem to be able to muster much.

 

[polymath]

Well suggest the key moieties required in an NMDA antagonist, suggest the key moieties of an opioid analgesic and suggest how the two could be reconciled within the BDPC scaffold.

A few opioids have some NMDA activity, but none seem to be able to muster much.

I don't believe it's possible to find that type of substances without many syntheses and receptor affinity tests. Maybe remove the N-methyls from a bromadol type molecule and put an N-ethyl there instead (like in PCE). As bromadol itself is a really high affinity mu agonist, the secondary amine version could still have some appreciable opioid effects. If it's possible to find that kind of substance that is an opioid and dissociative of similar potency at both, it's likely that the affinity to either receptor isn't that great and a typical dose is a quite large milligram amount. The problem is that then there can be more side effects caused by something other than the mu or NMDA effect.

 

[AlsoTapered]

Why don't you read the papers and patents concerning BDPC and related compounds. I happened to know Dr. Daniel Lednicer who developed the class so I know that many, many analogues were tested. In fact originally a simpler series was produced which while conforming to the ACA scaffold seen in PCP, K, MXE and so forth BUT required a ketone at the para position of the cyclohexane which utterly removed all NMDA affinity.

The work has been done, the results have published. There are at least 2 patents and 7 papers.

 

[polymath]

Why don't you read the papers and patents concerning BDPC and related compounds. I happened to know Dr. Daniel Lednicer who developed the class so I know that many, many analogues were tested. In fact originally a simpler series was produced which while conforming to the ACA scaffold seen in PCP, K, MXE and so forth BUT required a ketone at the para position of the cyclohexane which utterly removed all NMDA affinity.

The work has been done, the results have published. There are at least 2 patents and 7 papers.

I saw that Lednicer's article (or were there two of them) maybe 10 years ago and it seemed to contain a large set of compounds with opioid potency ranging from codeine level to the bromadol level. That 4-oxo-PCE is a strange compound if it's a pure opioid while not having 3 substituents at the nitrogen atom. You could try to put a hydroxymethyl or whatever to the para position instead to see if some substituent retains both NMDA and opioid activity.

Designing a combined opioid/NMDA drug, or any bioactive compound, would definitely not be my work task if I had an academic position at the moment, and it would be a large set of molecular docking simulations (instead of in vitro binding experiments) that I could actually do myself. It's more like computational applied physics I have done, sometimes related to biological matter.

 

[AlsoTapered]

I'm no sure I'm with you - could you draw it.

I mean, it seems clear that the initial idea was for a joint mu/NMDA but go through the tables.... nothing.

And I would appreciate a rationale of why you think a certain change will produce the desired effect. The Upjohn Drug Discovery team really were very, very good.

 

[polymath]

I can't remember whether it was PCE or PCP that became an opioid when a ketone was put at the para position (compared to where the aromatic ring and amine are connected) of the cyclohexane ring instead of where it is in the ketamine molecule. Looking at the IUPAC naming of ketamine at PubChem, it seems that this para-position of the cyclohexane ring is actually not labeled "4-position" after all, so I made a mistake there.

The para-hydroxymethyl version I suggested would look like this

And the para-ketone version of PCE is here (this is what was found to be an opioid instead of dissociative?)

But you could as well put a formylamide or esterified carboxyl in there, it clearly takes a large number of different compounds and affinity tests to get a good idea of the SAR.

In this article by Lednicer, the antinociceptive effectiveness was measured by tail-flick and other in vivo experiments instead of receptor binding (had the opioid receptors even been identified back then?). It's impossible to even be sure that the analgesic effectiveness of some of the listed compounds is not partly caused by NMDA blockage, and I don't believe anyone has tested for NMDA binding with all of these yet. Unless the patents you mentioned contain those results.

 

[sekio]

(had the opioid receptors even been identified back then?).

Apparently the opioid receptors were discovered circa 1973, so yes.[ref]
I don't think they had the same tools that we do now back in 1981, i.e. cloned HEK293 cells with specific opioid receptors cloned in so you can measure the affinity at each (mu-delta-kappa).

I cannot find any actual evidence that 4-keto-PCP is an active opioid at all. This paper seems to indicate that it's just a stimulating dissociative of its own.
The only reference for opioid activity seems to be a BL thread by adder describing bioassays, which need to be taken with a grain of salt and are no match for binding assays.

They could well just be NMDA antagonists.

 

[polymath]

At least there's this one where a 4-keto version is an opioid (but it has a tertiary nitrogen unlike PCE or ketamine, and no PCP like heterocycle)

4-Dimethylamino-4-(p-tolyl)cyclohexanone - Wikipedia

en.m.wikipedia.org

Afaik, if an arylcyclohexylamine has simple alkyl substituents on the amino group, there has to be only one (not two) to make it a dissociative, and N-ethyl is clearly the most effective.

 

[Skorpio]

At least there's this one where a 4-keto version is an opioid (but it has a tertiary nitrogen unlike PCE or ketamine, and no PCP like heterocycle)

4-Dimethylamino-4-(p-tolyl)cyclohexanone - Wikipedia

en.m.wikipedia.org

Afaik, if an arylcyclohexylamine has simple alkyl substituents on the amino group, there has to be only one (not two) to make it a dissociative, and N-ethyl is clearly the most effective.

I wonder if there is a limit for the bulk on the tertiary nitrogen for dimetamine. If I was doing SAR on that, I would look at N,N diethyl, N,N dipropyl, etc. And then look at smaller heterocycles than piperidine to see if there is some critical amount of bulk that loses mu activity.

Also I wonder if the phenyl ring needs that para methyl group. Maybe a 4 keto p-tolyl analog of PCP would display activity, as the BDPC analogs seem to want bulk at the para position of the phenyl ring.