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N&PD Moderators: Skorpio
What opiates have been proven in studies to be more desirable than morphine?
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I think nortilidine and the reversed-ester of same is worth commenting on. The trans pair have DRI activity as well (overlays (1R,2S)-2-Phenylcyclopentan-1-amine for everyone with Chemoffice) as opioid & NMDA activity. Plain tilidine is a prodrug but having read a dozen or so reports from a German site, the N-desmethyl metabolite looks desirable but is not particularly potent. I actually talked to the lead-chemist of the reversed-esters, Dr Derek P. Reynolds about it and he was open about saying he just used a god old plastic ball-and-stick model to check that the aromatic/oxygen lone-pair/positively ionizable function (the amine) had the same spacial relationship. I really should get back to him because with new routes known to the art, commercial precursor-->product is just 2 steps. People are generally happy to see a new route and he is retired so it isn't a commercial threat.Last edited:Limpet_Chicken
Bluelighter
Not the most addicting, just one that binds, has a long, long duration of action then destroys all the MORs it bound to.
It would be curious to see what a covalent-bonding biased agonist that doesn't recruit beta-arrestin 2 did though although I'd not try it myself, certainly not without testing it on stolen police officers first, or a whole load of islamists or politicians.The pharmokinetics seems to be a critical factor. The LogP & pKa says a lot about effects after parenteral administration. In the UK at least, some people are (maybe it's 'were' by now) prescribed 'wet' ampoules of methadone to treat heroin dependence. I know 'wet' morphine and 'dry' diamorphine ampoules are still prescribed but I have noted that the dual μ/NMDA agents are rarely prescribed in a form that lends itself to anything but oral/rectal dosing. Every nation seems to have a dual agent and in every country they seem to be considered the most desirable opioid for recreational use but I can remember the wakeup to Dipipanone diversion in the UK. They must show exceptional utility in refractive patient groups for their continued inclusion in a doctors armory.
It is always at the back of my mind that any compound that is active (i.e. must be soluble but unionized in the blood) has the propensity to end up being administered in every manner that makes it active. I suppose that is why I'm more drawn to compounds with a potency range around that of morphine (you can see a dose unit). Anything that also has limited scope for respiratory depression (I'm not sure if DRI/NRI activity inherently increases breathing) is also a good thing. Addition of BIMU8 (or other 5HT3/5HT4 ligands) to dose-units or provision of such agents in a HR manner would be interesting but I'm uncertain of the inherent safety of such agents. Fatal poisonings due to tilidine have been reported but the amounts involved were clearly from suicidal rather than recreational dosage. Grams of the stuff taken with alcohol or other CNS depressants. Taken alone, nortilidine appears to have stimulant rather than depressant activity.
It isn't my place to judge anyone's informed choice in taking any compound they want to, I would just like to see the safest option that fills the market needs. If the market accepts fentanyl, that is quite a clear message that less euphoric opioids are at least accepted. I appreciate that Gresham's law applies more precisely to opioids than any other financial sector and we aren't going to see things change at any point in the near future but we will eventually. Finding the safest solution for then is of interest to me. Not the money, just the changes in society.Last edited:
I'm sorry, but I hope this is a slip of the tongue and you are leaving at the word terrorists here right? Although I am not sure why you would be more prone to single out Islamic terrorists vs say neo nazis or white nationalists.Limpet_Chicken
Bluelighter
I mean the terrorist faction. And I just happened to pick that group because currently, the vast majority of terrorism is being comitted by islamist fanatics.
In human research (something I have 30+ years experience in), motivated subjects are the most useful. As a child, I was brought up with the developer-as-first-into-man paradym (family trade) and I agree with it. Medicinal chemists wouldn't be so bloody gung-ho about their research adventures if it were they who would stand to lose the most. I have lost medical cover and sickness benefit entitlement to remain a subject because I believe it should be my risk. I have often been annoyed by people taking my work and using it for profit but still much better than some adventure with an untested compound. I must be mentioned as a subject (not by name) in at least 2 dozen patents and for the people with GAD, pyrazolam at least proved it's worth compared with existing agents. It improved people's lives and that is MY buzz off 'drugs'.
Nortilidine is of marginal interest because it is so expensive to make (although I can accept beauty - The Diels-Alder reaction is amazing) for the potency and the original route to the reversed-esters is tedious. That, as of June 2016 we have access to a 2-step synthesis from a commercially available should be of interest. I've made quite a few opioids over the years and it is the SAFE ones that interest me. People will always find a way to poison themselves but we are in the position to make dose-units incompatible with alcohol (specifically) and CNS depressants more generally. We can make medicine safer but at a cost. While paracetamol + methionine is given to those seen as suicidal, OTC paracetamol isn't required to have methionine in it! Talk about short-sighted. If a drug doesn't improve or extend human life, why would we use it? We do this... I remain unable to see why.
i live in germany and was addicted to tillidine(obviously not nortillidine,which would be interesting to try)for over a year in sometimes doses exceeding 2 grams/day,and i can most definitely say that tillidine has no strong stimulant properties like say tramadol has(which i also took an awful lot,so i can compare them quite well)it is a moderately strong opioid,weaker than morphine or oxy,quite a bit stronger than tramadol or reasonable doses of codeine but pretty useless to someone addicted to heroin or other top tier opioids,other than helping a lot with withdrawing from stronger opioids.
It has a stimulant edge to it very much comparable to oral oxycodone,but without the strong euphoria,its onset is also slower than oral oxycodone,but faster than oral morphine.
The english wikipedia says 100 mg is comparable to 20 mg oral morphine,but i would say 100 mg tilidine is comparable to 40-50 mg oral morphine,because of morphine terrible oral bioavailabillity(which is actually a godsend to me,because i get oral morphine as maintainance drug and i get 600 mg oral morphine a day for take home(which means i get a whole week worth of morphine once a week)and when i decide to shoot u,which i do very rarely,600 mg morphine is suddenly very,very much because 600 mg iv morphine is like 3 grams of oral morphine and i can make 5-6 hardcore bangers out of one day worth of morphine,thats why i stocked up alot of morphine.
I now have over 40 grams of morphine laying around (over 200 200 mgs morphine capsules which beads are easy to crush )Last edited:It didn't seem that you took any, but just wanted to iterate that I meant no offense in questioning your word choice, I assumed it was as I stated but in the past I have been surprised more than once that otherwise seemingly intelligent, rational people who's opinion I respected were actually harboring racist world views unbeknown to me for some time. And while its definitely the norm globally to think of terrorists as Islamic, especially in Europe, in the US white nationalist terrorism is a much bigger problem(although you may not realize this if your main source of information is the MSM).
BTW, your inbox is full.
Tilidine and nortilidine are 2 different compounds. To produce stimulation, I seem to recall that ⅔ of the central dopamine receptors need to be occupied and since nortilidine has a higher affinity to the opioid receptors, it's only when a sufficient amount is available to highjack the VMAT2 transports that such levels can be reached. Consider dimethamphetamine and methamphetamine. Codine and morphine. Or, much closer - pethidine and norpethidine. Pethidine is an opioid, norpethidine is a stimulant. The 'magic methyl' is named such for a good reason.Limpet_Chicken
Bluelighter
Isn't norpethidine a 'stimulant' under some other mechanism than monoaminergic? because its a convulsant.
It is a DRI.
Lorne???
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Interesting thread
And a complicated question: You mean RC effects, or analgesic, etc?
And btw, when equipotent doses of Morphine Classic and Heroin were administered at a gradual rate(IV), subjects effectively showed no preference
Technically, no study has proven any opioid more ?desirable ? per say, although for analgesia, it is known IV oxycodone Bolus has less side effects and takes effect almost immediately, vs morphine, which has a delayed peak, even with intravenous administration-(15-30 supposedly, onset is rapid with RC doses, with lower doses it can take several minutes)
For analgesia, methadone is better for certain types of pain, and methadone and morphine are still pretty much considered the analgesic heavy hitters AFAIK, and certainly, along with diamorphine, would be my choice for chronic pain
Oh, and oxycodone has a mean BA% of closer to 50%; Morphine BA%(or potency) increases with chronic administration, and is likely somewhat dose dependent, and variable, though like 15-40%? ( Dianorphine reaches 50-70% with chronic administration of high doses)
30% is a reasonable figure
Tge exotic opioids are a different story- ok sorry to interrupt
Interesting thread
And a complicated question: You mean RC effects, or analgesic, etc?
And btw, when equipotent doses of Morphine Classic and Heroin were administered at a gradual rate(IV), subjects effectively showed no preference
Technically, no study has proven any opioid more ?desirable ? per say, although for analgesia, it is known IV oxycodone Bolus has less side effects and takes effect almost immediately, vs morphine, which has a delayed peak, even with intravenous administration-(15-30 supposedly, onset is rapid with RC doses, with lower doses it can take several minutes)
For analgesia, methadone is better for certain types of pain, and methadone and morphine are still pretty much considered the analgesic heavy hitters AFAIK, and certainly, along with diamorphine, would be my choice for chronic pain
Oh, and oxycodone has a mean BA% of closer to 50%; Morphine BA%(or potency) increases with chronic administration, and is likely somewhat dose dependent, and variable, though like 15-40%? ( Dianorphine reaches 50-70% with chronic administration of high doses)
30% is a reasonable figure
Tge exotic opioids are a different story- ok sorry to interrupt
All good points. From HR work, reports are that Diconal is renowned to give an almighty rush when IVed (lasting 10 minutes, not 10 seconds) and from reports on ketobemidine, piritamide & levorphanol - that long, super-euphoric rush is the hallmark of the μ/NMDA-antagonist agents. I know that people have even increased the μ/NMDA rush by adding cocaine or (apparently even more euphoric) methylphenidate. Adding antihistamines to a shot (Diconal is 10mg dipipanine/30mg cyclizine) like pentazocine/tripelennamine (Ts & Blues) or morphine/tripelennamine (Blue Velvet) and even ersatz Diconal (methadone & cyclizine) has a long history.
Just a few years ago, a pharmacist on the Isle of Wight got 3 years for selling some 125 thousand cyclizine tablets. While technically a [P], none of the pharmacists I know stock the stuff - they more or less know that it is 100% diverted by H dealers who either sell them for the users to bash into their fix or even more dubiously, they add the cyclizine unknown to the users. The dealer selling H bashed with cyclizine will ALWAYS be in huge demand. Denying people informed choice is more troubling to me that the supply of known agents.
It isn't awfully difficult to come up with a potent μ/NMDA agent if you know the QSAR of certain series. Etonitazene is actually only x60 M in mammals but some German researchers stumbled onto a μ/NOP/NMDA ligand. They didn't have the software (Chemoffice, Discovery Studio) to examine the stuff and overlay it with other compounds but as part of some research I spent a couple of days on it and the derivative overlays both MCOPPB & piritamide. Lo and behold, it exhibited analgesia in μ-knockout & (to a lesser extent) μ/NOP-knockout mice supplied by Jackson. I hasten to add I deplore animal testing and reduce, refine, replace is the way to go...
But in fact the Eunoia disc has a whole directory of the stuff. Whoever built the disc played with the directory structure so that you could reach folders from more than 1 parent directory.... How is that done? I've never worked out how....
TheJuner
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Yes, it really is that much better than oxycodone. Make sure you try it intranasally though, that's how I knew that it really did live up to its hype and I had used oxycodone intranasally and orally many times prior and in comparison, oxymorphone is in a tier of its own in terms of how overwhelmingly euphoric it is. It's less energizing than oxycodone, though, it feels more sedating and 'dopey' which I personally love about it. It's euphoric, analgesic, and sedating effects remind me a lot of diamorphine, but its euphoria feels more intense ime. Also it has amazing legs and an amazingly euphoric rush.
4DQSAR
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Since 'desirable' is an entirely subjective term, how does one measure it?
I have noted a pattern in that almost no opioids more than a magnitude more potent than morphine seems less peferred by users.
I suggest the reason is that the subjective 'euphoria' is driven by the binding-unbinding cycle so any opioid with a long mean occumancy time will produce less euphoria.
Janssen was probably the most prolific with Hoechst in second place. Between them they discovered hundreds of opioids. Over the years Nathen B. Eddy is probably close to Hoechst but he tended to synthesize semi-synthetic rather than fully synthetic opioids.
Between those three groups almost every compound mentioned. Yes, oxycodone was earlier and yes, norilidine was later but both examples MAY be preferred no because of their opioid activity but rather because they have multiple actions that combine to produce an ASC not quite the same as those produced by ligands that purely act on the opiate receptors.
First Janssen synthesized THOUSANDS of compounds related to methadone and stated that he chose to move to the phenylpiperidine scaffold because the synthetic complexity of the 3,3-diphenylheptanones and specifically the fact that many had rather narrow theraputic windows so could only be used when a single stereoisomer was isolated.
But between those three around 90% of the 3,3-diphenylheptanones, phenylpiperidines and morphinans were first synthesized by one of those three.
For whatever reasons the UNODC took the unusual step of stating ketobemidone to be unique in that the AWS could be fatal. I see no evidence of that but if one carefully looks at the dose-response curve of ketobemidone, it becomes apparent that non-medical doses could have been far more powerful than typical studies would identidy so it may be the case that the deaths were no a direct result of ketobemidone AWS but more clinicians simply not understanding that the user consuming 100mg of ketobemidone a day. It may also be the case that at non-medical doses ketobemidone acted on other sites. It's NMDA activity was identified quite early in it's development but maybe if the dose-response curve of it's opioid activity weren't well establishes, neither was it's NMDA activity?
That's the problem.
Almost all of the mose sought after opioids are now either no longer in use or at least have become far harder to acquire and of course sinse their respective patents are now a distant memory, few modern researchers could really study them even if they wanted to.
I'm old enough to remember the UKs Palfium crisis and it's Diconal crisis both of which were products of Janssen being less than honest about the oral bioavailabilty. I found an original ad for Palfium from 1955. An ad targeted at clinicians. One of the selling poins was 'high oral bioavailability' when we now know it was only about 20% so obviously addicts injected them but while swallowing a 'peach Palfium' or two produced a rush (rare for an oral opioid), the reasons why it demonstrated that unusual action was a function of it's physical properties so a lot of users who were stuck with two peaches could swallow them to stave off AWS or inject them... which often ended in a very fatal manner.
But U-47700 was selected even when BDPC was an alternative because it was preferred and so this does appear to bear out the idea that for whatever reasons, opioids with only moderate affinity seem to consistantly be preferred to opioids with extremly high affinity.
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I would love to try palfium and diconal but they where never available on the Canadian market at all. Honestly i dont think it gets much more euphoric then IV diludid anyway. That has a stronger but shorter lived rush compared to morphine
Rectify
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What Do You Mean By “Desirable”?
It Just Depends On What You Are Looking For. For Example, I Enjoy The CEVs Of DXM Salts, But Have At Times Puked From OxyContin Or Felt A Rush From IV Heroin As I Carefully Injected It Into My Vein. Tbph, The Opiates Are Death Drugs, But They Are The Only Way I Know How To Really “Chill.” Hydrocodone Seems Pretty Harmless To Me. But Many Pharmacies Can Sell You Codeine In The Form Of Robitussin AC If They Want To. Dextromethorphan Is OTC, But It May Or May Not Even Count As An Opioid Structurally Or Pharmacologically.
4DQSAR
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Well, just off the top of my head, everyone I know who sampled both hydromorphone and oxymorphone firmly stated a preference for the latter. In fact they complained that all hydromorphone had was a rush and then nothing whereas oxymorphone had the rush and the ongoing euphoria.
I think the flash (the correct name for the 'rush' of an opioid) is when a ligand has a relatively low LogP but that value hides the fact that it's highly soluble in both blood and fat. Heroin is a good example. It's salts are freely soluble in water but when deprotonation takes place, it's increased lipophilicity (compared to morphine) means it crosses the BBB very quickly.
Apparently this subtle difference is also why desomorphine was discovered, introduced (in Switzerland) but fell out of use within a handful of years. For clinicians the problem is that fast onset appears to introduce risk.