Pharmacology Tilidine - Pharmacology and chemistry

[Hexenstahl]

God I'm spending too much time on pubchem again, looking and comparing chemical/physical properties and formulas and structures between various opioids lol. I'm going to dedicate this thread to the humble and incredibly underrated, almost unknown Madame Tilidine, which has an equianalgetic potential of only ~0.1 - 0.2 compared to morphine, but is THE most euphoric opioid I ever had the pleasure of trying while still in my opioid naive phase 12 years ago (back then I tried everything from codein, to tramadol, to DHC from a famous british brand which an english friend of mine smuggled to Germany for me while visiting me, and finally to Tilidine which I loved more than anything else). In fact Tilidine is so notorious here in Germany for its euphoria and lack of sedation, that the german-swiss drug forum "Eve & Rave" has an entire thread dedicated to questions and discussions surrounding that opioid back from 2007 spanning 389 pages to this day! That's how popular it is here!

Now, this fully synthetic opioid has quite an interesting skeletal formula which reminds me a bit of Levomethadone, but it's kind of diagonal (this has to be one of the most unscientific descriptions that I have ever come up with lol, but I'm lazy right now, so please cut me some slack).

This is the 1:1 stereoisomer mixture of (1S,2R)-Isomer (left) und (1R,2S)-Isomer (right). The 2-(Dimethylamino)-1-phenylcyclohex-3-en-carboxylic acid-ethylester has two stereogenic centers. So there are actually 4 stereoisomers: The enantiomeric (1R,2S) and (1S,2R) form, as well as (1R,2R) and (1S,2S). Tilidine is a racemat which is made out of the enantiomers (1R,2S) and (1S,2R). The importance of enantiomeric purity has become more and more important over time it seems, because the enantiomers of chiral drugs (almost) always show different pharmacological and pharmacokinetic profiles. Just to give you an idea of how the slighest deviations in purity can have an enormous impact: the trans-form has twice the activity than the cis-form (which isn't commercially used for obvious reasons) and that only because the cis-racemat has an impurity of 0.5%!!!
The (1S,2R) enantiomer [(+)-trans] is a whole lot more stronger in terms of activity than the (1R,2S) enantiomer [(−)-trans] (ED50 is 23:1 when s.c. ROA is applied).

Tilidine itself is actually a prodrug. It is only when the liver enzymes remove a methyl group from the molecule, turning tilidine into nortilidine, that turns the drug into a psychoactive opioid. Nortilidine is an incredibly fast acting opioid with effects already setting in within 10 to 15 minutes (oral ROA). When I took the Tilidine oral solution I started to feel the first effects within that time period. Interestingly though, the effect wears off quite slowly.
Papers say that Tilidine has no antitussive effect but I disagree. I have found the antitussive effect to be quite weak, but it's definitely there.

Now, I don't know much about the synthesis of this wonderful opioid, but the precursors are quite interesting. Crotonaldehyde and dimethylamine are turned, with atropic acid ethyl ester, into dimethylaminobuta-1,3-dien via the Diels-Alder-Reaction. I don't know the steps involved to turn the latter compound into Tilidine though.
Let's look at crotonaldehyde and dimethylamine. The former precursor is found in a plant called "Croton". This plant has an oil, the croton oil, which can be turned into crotonaldehyde. What's interesting is that this substance is also found in the human body. Polyamines turn ethanal into crotonaldehyde after alcohol consumption.
This precursor is highly flammable, with a strong, piercing smell, is very hard to solve in water (better solubility can be achieved in organic solvents) and tends to build peroxides and atoxidation in the presence of oxygen.

Dimethylamine is also an interesting precursor, not because of how it is synthesized or used, but due to the fascinating and yet relatively unknown fact that it is found in cannabis smoke. If the %-composition of DMA is big enough, cannabis smoke could be used as another source to produce DMA (if self-grown, otherwise it's too expensive ofc).

All in all, Tilidine is a very interesting opioid, both chemically as well as psychopharmacologically. If I wanted to synthesize a potent opioid with a strong euphoric response, I'd look towards Tilidine as a potential candidate and further manipulate it chemically to increase its analgetic potency. Tilidine as it stands today is simply too weak potency wise, but has a lot of potential if a pharmaceutical chemist had the interest and determination to create a much more potent derivative of this opioid. I think I'll do that in the future

 

[AlsoTapered]

US issued 4291059

The above is a reversed-ester analogue of tilidine and nortilidine. I actually tracked down the inventor (Derek P. Reynolds) and asked him about the research. It was a fascinating insight into QSAR prediction.

The problem with BOTH scaffolds is their cost when compared to their potency. Nortilidine and Isonortilidine (for want of a better name) are the active drugs. It's unusual to find a secondary amine having much higher affinity than the co-responding tertiary amine but it appears both tilidine and isotilidine are both entirely prodrugs (at medical doses).

Why not try overlaying nortilidine or isonortilidine with cypenamine - THAT is why they both demonstrate DRI activity.

Or, for an even better overlay, try N-methyl cypenamine.

(1S,2R)-N-methyl-2-phenylcyclopentan-1-amine

(1S,2R)-N-methyl-2-phenylcyclopentan-1-amine | C12H17N | CID 89089192 - 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

Now why the (1R,2S) enantiomer of both compound demonstrate NMDA activity is also interesting.

 

[izo]

Yeah tilidine seems only to be a prodrug for n-desmethyltilidine which is secondary what is really rare in the opioid world. Almost all opioids show full activity when their Amine is tertiary. Also tilidine seems to be more of an European thing. Never heard of any country outside the eu where it is prescribed. For me tilidine felt exactly like a methadone light compound, nothing special in the opioid world but a good solid light opioid. It has gained some attention as the drug of choice for the younger rapper crowd that seems to abuse the shit out of it. It was originally invented by Gödecke, right?

 

[AlsoTapered]

Yeah tilidine seems only to be a prodrug for n-desmethyltilidine which is secondary what is really rare in the opioid world.

It is rare but not unique. Don't forget that it's not the basic nitrogen itself that is key to activity but the orientation of the lone-pair. In the 1950s studies were carried out with quaternary salts of morphine (e.g. morphine methiodide) and with N-oxides. Both of those derivatives result in a chiral centre and it was discovered that one enantiomer was an agonist, the other an antagonist. Of course both of those carry a formal charge so cannot cross the BBB so their activity was only seen with in vitro testing.

With nortilidine the O right next to the N, the orientation of the lone-pair is fixed due to interactions with the O lone-pairs.

The few other opioids that are secondary amines and their are even a few primary amines. Most of these appear to displace mixed activity being able to bind in both agonist and antagonist conformations BUT the N-substituent INCREASES the chances of them binding in agonist conformation. Oliceridine and similar are examples.

I absolutely do not believe in all that 'biased agonist' theory. The Chinese spent a decade researching it and discovered all they had were low efficacy ligands. The research even resulted in the RC brorphine - but I've read no reports on that compound and suspect that in fact it's a NOP ligand so not much fun.

 

[Hexenstahl]

Yeah tilidine seems only to be a prodrug for n-desmethyltilidine which is secondary what is really rare in the opioid world. Almost all opioids show full activity when their Amine is tertiary. Also tilidine seems to be more of an European thing. Never heard of any country outside the eu where it is prescribed. For me tilidine felt exactly like a methadone light compound, nothing special in the opioid world but a good solid light opioid. It has gained some attention as the drug of choice for the younger rapper crowd that seems to abuse the shit out of it. It was originally invented by Gödecke, right?

Yeah everyone reacts differently to the psychoactive effects of opioids, but statistically speaking it's hands down the most liked opioid in Germany.

Also, don't get me started on those ignorant, uneducated, irresponsible rappers with their lean, tilidine and all that shit. They promote shit they don't understand in the slightest. My inner conspiracy theorist sometimes wonders if those are cases of pharmaceutical corporations illegally marketing their habit forming drugs in underhanded ways by working with big name labels (who own the souls of those poor musicians btw) to make those rappers produce songs about drugs and create a fascination with these substances in young, impressionable minds. I know I can't prove it, but it makes sense to me considering how predatory this industry is.

 

[AlsoTapered]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Just to compare, here are the active enantiomers of nortilidine and isonortilidine.

Like the cathinones, the N lone-pair interacts with the O lone-pairs so that the N: exactly overlays that of morphine... which both of the above compounds actually partly overlay.

 

[Hexenstahl]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Just to compare, here are the active enantiomers of nortilidine and isonortilidine.

Like the cathinones, the N lone-pair interacts with the O lone-pairs so that the N: exactly overlays that of morphine... which both of the above compounds actually partly overlay.

There is something I don't understand: why sell this opioid as a prodrug and not directly produce the active metabolite nortilidine? Is it due to financial reasons?

 

[AlsoTapered]

Well, if you look at the patents or other papers that detail the synthesis of tilidine, you will note that it's very simple but elegant. It's a convergent synthesis (so has molar efficiency) BUT it cleverly uses a Diels-Alder reaction to condense (1E)-N,N-dimethylbuta-1,3-dien-1-amine and ethyl atropate.

Now the Diels-Alder will only work with a tertiary amine. Their are later papers in which Br2 is used to N-monodemethylate to nortilidine but it's yield isn't amazing so for a given amount of analgesia, tilidine worked out more efficient than nortilidine. It being a prodrug was also likely a safety advantage and it represented a handy gap between the potency of dihydrocodeine and morphine. Yes, meperidine is also cheap but has significant sife-effects.

Isonortilidine IS a simpler target than isotilidine but when you look at the patents you realize that overall yield is still only about 40% and be it tilidine (ethyl atrophate) or isonortilidine ((cyclopent-1-en-1-yl)benzene), each requires a rare and costly precurssor.

Believe me, about once a year I go through the latest research to see if their is anything new that would make nortilidine a facile target and every year I fail.

That is the lot of the RC dessigner. It has to be both facile AND legal which can be tricky.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Try overlaying bea prodine with U-47700 and note how everything overlays and both compounds are about 7.5x M in potency. Then look up allylproding and try overlaying it with U-93951. See, once again they overlay perfectly. So that along with some other calculations sugest that the Upjohn derivative will also be some x23 M. Now that can afford to cost a little more is 5-10mg represents a £10 dose.

 

[Hexenstahl]

That is the lot of the RC dessigner. It has to be both facile AND legal which can be tricky

Good luck getting a novel opioid approved as an RC chemist lol.
This is why I would register as a pharmaceutical company if I was going to synth opioids and buy the necessary precursors as they have totally different regulatory rules applying to their legal entity.
The only thing which prevents that crucial step is capital. I'll first see to it that I get an expert understanding in chemistry first, and then later on down the road I can write a sound business plan with financial projections, drum together a couple of entrepreneurial people and present the plans to as many banks as possible who will hopefully lend us enough capital to actually start a legitimate and respectable pharmaceutical corporation and not some shady RC shop. I shouldn't be in such a hurry though. I'm young after all and got plenty of time...

 

[AlsoTapered]

The costs of developing any new medicine are vast. On average $2.8 billion. It's also an average of 13 years between initial patent and market licence.

So unless you can design an opioid with an obvious clinical advantage, why would a doctor ever consider prescribing it? I do no know what WOULD be seen as sufficient advantage to supplant codeine and morphine.

With RCs obviously safety still comes first, but then it's legal status and finally (and often the deal breaker) cost per dose. In two years I managed to get about 20 new RCs onto the market. In the mainstream industry I can point to multiple researchers who spent an entire 40 year career purely working on novel opioids without a single product reaching market.

In fact, the vast majority of medicinal chemists never designed a successful novel medicine in their whole career. Most patents are not for new medicines but improved syntheses and new formulations of existing medicines.

QUITE often an RC is a combination of a known active modified using rational design and 3DQSAR that conveniently can be made simply. The MOST profitable product could be made in one simple step from very cheap reagents in a high yield while much more sophisticated and thus potent ligands were actually LESS facile.

A lot like medicines, the success of an RC is very much luck. Pyrophenidone is a bioisostere of pyrovalerone and is actually better than the original but was never a great success because at the time cathinones were cheaper. I believe now people are beginning to make it but on the whole it was a waste of effort.

Diphenidine which was just the prototype was hugely successful to the extent that everyone totally ignored isophenidine which is much better. Whatever the market, it's hard to ensure success unless, like some of the 'blockbuster' medicines, a LOT of unethical (but not technically illegal) promotion went on.

 

[Hexenstahl]

In fact, the vast majority of medicinal chemists never designed a successful novel medicine in their whole career. Most patents are not for new medicines but improved syntheses and new formulations of existing medicines

I'm aware of this. The design of a novel opioid is more of a private, personal objective of mine. The improvement/modification of an existing opioid is both from an economical and temporal perspective much more feasible than sitting god knows for how many years in the lab trying to come up with a novel opioid that has a competitive advantage while the interest on the corporate debt keeps on accumulating.

Whatever the market, it's hard to ensure success unless, like some of the 'blockbuster' medicines, a LOT of unethical (but not technically illegal) promotion went on.

Hehe, never underestimate the power of kickbacks. But yeah, we probably have to reinvest the majority of our cash flow into the most aggressive marketing campaigns that are legally possible, a good portion for patent and intellectual property acquisition since that is the primary driver of market value in the pharma sector (and sometimes it's just better to use inventions and innovations others have come up with), while using only a conservative amount of the CF for R&D. Not saying R&D is useless, but it takes time to fall on fertile ground and deliver satisfying results. Most start ups have unreasonable R&D expenses and by the time they have come up with a financially valuable patent they can only get a fraction of those costs back in, and that's what often causes them to fail. I'd like to avoid that...

 

[AlsoTapered]

Well, I cannot fault your sheer scope of intent.

But don't forget - just because you can draw a molecule is no guarantee that their will be a practical synthesis.

 

[Hexenstahl]

I had an interesting idea today. Designing an opioid compound that is like Vyvanse in the sense that it has an extended release mechanism built into its molecule would definitely give one a competitive advantage. The ER mechanism can't be circumvented by crushing the pills. So many good ideas, so little opportunities to execute them...

 

[AlsoTapered]

It's worth checking PubChem - I've had so many novel designs only to discover that someone stole the idea and went back in time 40 years.

The N-oxides and various other things have been tried and obviously things like codeine and tilidine are pro-drugs relying on liver enzymes to convert them into the active.

The problem with all prodrugs is that activity can differ hugely between ethnic groups. I guess the most well known example is African Americans who are super-metabolisers (high CYP2D6 levels) so drugs like codeine and tramadol are much more active.

 

[emkee_reinvented]

Yeah everyone reacts differently to the psychoactive effects of opioids, but statistically speaking it's hands down the most liked opioid in Germany.

Also, don't get me started on those ignorant, uneducated, irresponsible rappers with their lean, tilidine and all that shit. They promote shit they don't understand in the slightest. My inner conspiracy theorist sometimes wonders if those are cases of pharmaceutical corporations illegally marketing their habit forming drugs in underhanded ways by working with big name labels (who own the souls of those poor musicians btw) to make those rappers produce songs about drugs and create a fascination with these substances in young, impressionable minds. I know I can't prove it, but it makes sense to me considering how predatory this industry is.

Since reading "Kinder auf them Bahnhof" or Christianne F. the drug always fascinated me. Being EU myself I say its a German thing unknown over here.

Sounds like dextromoramide, an outdated drug now but not in the 70's ( or '98). Euphoric, fast hitting and orally active. Dr's prescribed it to Heroin addict's, IV-ers. Harm reduction at that time.

 

[emkee_reinvented]

I had an interesting idea today. Designing an opioid compound that is like Vyvanse in the sense that it has an extended release mechanism built into its molecule would definitely give one a competitive advantage. The ER mechanism can't be circumvented by crushing the pills. So many good ideas, so little opportunities to execute them...

Dexedrine imo felt like a very smooth come up and down, no need for extended release.
I was used to that garbage dl-Methylphenidate which its roughly 2 maybe 2 and a 1/2 hour of action, fast come up and drop off and then the rebound. Also sleeping was hard on it. So I was popping about 10 mg every 3 hours to sustain an awfull stimulant.

Dextro-Amphetamine was a true relief, the IR's. Where to me non abuseable, unlike it dl- cousin Speed. Never had sleeping trouble on Dex too. While dl-Amphetamine kept me awake all night.

 

[Hexenstahl]

Sounds like dextromoramide, an outdated drug now but not in the 70's ( or '98). Euphoric, fast hitting and orally active. Dr's prescribed it to Heroin addict's, IV-ers. Harm reduction at that time.

The issue with dextromoramide is that it's relatively short acting. Sure, the biphasic hl can last up to 22h, but the psychoactive effect of the active metabolite is quite short. People often erroneously think half life equals duration of action. Its long hl guarantees that you won't enter wd for 22h (depending on whether or not you're a fast metabolizer), but the actual duration of action of dextromoramide is quite short and therefore not suitable anymore for maintenance since we have better options. However, those better options are unfortunately completely unavailable for americans (Substitol which is a 24h acting morphine pill and Polamidon which is Levomethadone-HCl, the non-cardiotoxic and even longer acting opioid compound than Methadone) and the vast majority of the world in general. Swiss people have it even better. They have access to extended release heroin pills (Diaphin).

Dexedrine imo felt like a very smooth come up and down, no need for extended release.
I was used to that garbage dl-Methylphenidate which its roughly 2 maybe 2 and a 1/2 hour of action, fast come up and drop off and then the rebound. Also sleeping was hard on it. So I was popping about 10 mg every 3 hours to sustain an awfull stimulant.

Dextro-Amphetamine was a true relief, the IR's. Where to me non abuseable, unlike it dl- cousin Speed. Never had sleeping trouble on Dex too. While dl-Amphetamine kept me awake all night.

There are ways to increase the onset of action of dexedrine, so there is definitely a need for an ER formulation. Well, chemically speaking, all of those compounds are rather boring in my humble view. The only amphetamine that I find truly worth studying is Lisdexamphetamine Dimesylate. I'm trying to figure out since days now what exactly it is in the molecular structure of Lisdexamphetamine Dimesylate which causes the "natural" extended release pharmacokinetic property without the physical alteration of the actual pill to guarantee the ER property. Figuring that out and trying to find methods and possibilities to translate that pharmacokinetic property onto an opioid (basically designing an opioid version of Vyvanse) is an actually worthwile R&D project for which I'd grant a massive budget if I was the CEO or executive chairman (or chairperson if we are supposed to use pc language these days...ugh). Such a vyvanse-like opioid patent would generate billions of dollars in revenue since that'd be the first opioid which is completely impossible to de-retard and the healthcare industry has a desperate demand for such an opioid. 20 years exclusive rights for the sale of such a product...mouth watering

 

[someguyontheinternet]

When it comes to lisdexamphetamine its really just metabolism. Cleavage of amide linkage is slow and only takes place in the liver (maybe also gut? Idk) but esters can be cleaved in plasma. That's honestly all it is, metabolism takes time.

 

[AlsoTapered]

There is a truism taught to both pharmacists and medicinal chemists - 'There is no such thing as an Sustained Release formulation' i.e. nobody has ever managed to produce a formulation that ensures a steady plasma level for a medicine. That's why more modern forms of the concept are referred to as 'Extended Release'.

For lisdexamphetamine their are various graphics which show the plasma concentrations of dexamphetamine and essentially 100mg of lisdexamphetamine has a curve almost identical to 40mg of dexamphetamine but shifted right by about 60 minutes.

Dextromoramide is an old drug and it's really unusual in that their are no closely related compounds with anywhere near the same amount of activity. It's a tiny island of activity. It's discovery was long before we understood how psychoactive drugs really worked but the speed of onset suggests that active transport is involved.

 

[Hexenstahl]

nobody has ever managed to produce a formulation that ensures a steady plasma level for a medicine.

Interesting, I must have hallucinated the steady release of the morphine when I took my Substitol back in September and felt a 24h relief due to its slow release. Entire papers have been written on how the steady release formulation of the nearly indestructible beads (I have tried to de-retard Substitol multiple times, with no success. Perhaps I can try dropping a truck on it next time. They are as hard as a rock) works on maintaining near constant blood plasma levels and how that makes it possible for any opioid to be used as a maintenance drug. Claiming that there is no such thing as an ER formulation is completely absurd. Sure, there is none built in to the molecule of any opioid, which is why I wrote how revolutionary it would be if someone invented such a molecule, but there are multiple, physical pharmacokinetic techniques that ensure an ER of a DOC, from the osmotic release system (OROS technology), with a small but sufficiently noticeable part being released immediately and the rest over a more sustained period of time, to the multiarticular beads release technology that uses a 50/50 release approach.

Btw, sustained and extended are sometimes used interchangeably and sometimes the latter is used as an umbrella term. Pharmaceutical companies all have their own definitions of what they mean since those terms are neither protected nor scientifically defined in any clear and uniform way.

There is a truism taught to both pharmacists and medicinal chemists

That's not a truism that's nonsense. Sorry if that sounds harsh, but it's just not true. Several pharmaceutics uni textbooks have entire chapters dealing with the science behind ER/SR technology. It's an extremely complex subject matter that deserves its own subfield of science.
There are entire drug research departments of large, multinational pharmaceutical corporations that do research specifically on how to come up with better formulations. There is an actual science behind it...