Pharmacology Tilidine - Pharmacology and chemistry

[DeathIndustrial88]

I'm actually considering deleting this thread just like I did with the other two science related threads I created, because sometimes I sometimes feel like this forum doesn't deserve such threads. I mean just look at the replies. For god's sake, instead of all coming together (regardless of anyone's level of knowledge, we are ALL lifelong students.) and COLLABORATING together (the real reason I have created these threads) to discuss, discover, ask, answer and perhaps even create something together, it ends up becoming a childish dick-measurement contest where people just try to show everyone else how right they are and just how much they know in more or less subtle patronizing ways. If then someone dares to voice legitimate criticism, various logical fallacies are used, from appeal to authority to the accomplishment fallacy (muh experience, so shut up you greenhorn), and the worst of all: straight up LIES! Putting words and intentions into my mouth that I have NEVER actually said or meant. A forum with such members does NOT deserve such threads. I'm gonna take these things to an actual chemistry and pharmacology forum (there is a good german one I know of, even though it has like only 5 active members, but at least they are humble and open to being corrected despite having a billion years of experience under their belt, which btw doesn't protect you from being wrong) which is a place better suited for such discussions where people actually collaborate together.

Also funny how AT told me the entire time how ER/SR doesn't exist and is merely a "political" designation, but then when Skorpio literally said the same thing that I said (OROS System) he suddenly turned around and was like "oh uh yeah, that OROS thing...pretty cool stuff mate". So the exact same thing you told me happened in that bupe thread and why you eventually stopped replying to such an hopeless case has repeated itself here. These kind of things just show me that there is some personal ego stroking shit going on behind posting such "educational" replies here and not an actual desire TO TEACH AND BE TAUGHT IN LIKE MANNER.
I think I'll sleep one or two nights over this and then decide whether or not I delete this thread. I have copied my entry post and translated it in german in case I do delete it so I can then post it in the german pharmachem forum.


Hey no hurries buddy. Take your time, ok? It ain't like I'm sitting here all day and wondering when doomy-gloomy deathy industrially (hehe I like to cutify other people's names...tehehe ) will finally reply to my emails. So chiiiilllllll


EDIT:
earlier I said "A forum with such members does NOT deserve such threads". That was perhaps not really fair, as 99% of all members I have talked to here ever since I registered are completely fine. It wasn't my intention to generalize. It's just that the remaining 1% are very vocal and acive and can make or break a thread. That's what I wanted to say and not that BL as a whole is responsible. You guys are great, especially the staff!

My vote is to definitely sleep on it a night or two.
I think there's still some non-confrontational people here who can benefit from the information provided here.

I've actually lurked on BL for the past 10 years but only a made an account within the past few years. So there could be countless people out there gaining insight from things who aren't even active on here as well.


But in all honesty, I'd completely understand why you would. Especially if it keeps going the way it's going. It's kind of ironic that I told you that this is what people do & then it basically happened to you too. People trying to tell me I'm wrong about shit left & right, only to say the exact same thing I said (just slightly different) in another reply. lol I don't get it at all. I have absolutely zero problems with being educated or told what's right or correct as I enjoy learning (to the best of my ability) anyway but that's not what's actually happening here. Just people needing their ego's stroked to the point where they're willing to deflect & even just make shit up. lol

Awe, but I want you to wonder about me!!!
Just left you another novel to read!! I enjoy getting back to you anyway! I was even gonna keep going haha But then you'd have too much stuff to respond to, so I'll chill. lol

Off-topic : I made $50 bucks yesterday selling cassettes I made. But now I have to go to the damn post office & stand in line for 20hrs to send it out. lol Hoping it goes well cause I definitely don't have the patience to deal with the public today.

 

[Hexenstahl]

The context was dose dumping in terms of consuming the pills with alcohol not that it was creating a constant plasma concentration. Dose dumping in this context is defeating a mechanism that slows release.

You still don't get it (or don't want to get it, which is what I suspect since you aren't stupid and obviously understand my actual message): I have NEVER in this thread ever claimed that ER is supposed to guarantee a constant plasma concentration. That is ONE definition, which AT is deceptively implying to be the only correct industry-wide accepted view that is challenged by no one and those that do obviously suffer from dunning kruger, what else, right? The truth is that nobody outside of theoretical armchair academics gives a shit about this, when ER formulations cause a drug to be released so slowly that the patient feels a constant effect. It is completely and uttely irrelevant if that is on some mathematically abstract level not true if it bears no felt consequences in the real world beyond paper and ink.

Substitol for example has a unique ER formulation that is patented by the only company that sells it, and that formulation is so efficient that it releases a psychoactively sufficient amount of morphine one hour before its half life has been reached to guarantee a steady PERCEIVED effect. We all noticed this every time we took those pills. I felt a little nod every three hours (one hour before the 4h half life mark was reached) which indicated that my blood plasma concentration had been increased. This happened every 3h for a total of 24h, making 8 PRRs (periodical release rounds) which the drug achieves by having layers of morphine beads with differing density, size, retardation coating, etc.
That is the generally accepted, working definition of what constitutes an extended release/sustained release drug. In case you don't know what the definition of "working definition" is: a plan, idea, or knowledge that is not complete but is good enough to be useful or generally accepted.
So for the pharmaceutical markets, doctors, patients and the healthcare industry in general THIS definition, THIS type of ER mechanism/behaviour is good enough to be accepted and therefore considered ER/SR. Whether or not blood plasma levels can be maintained 100% of the time with no material excess variance is IRRELEVANT. Nobody cares.

I hope I have finally explained my case clear enough and used enough repetitions so that you and everyone else understands what my stance on ER is. This is a thread about TILIDINE and not ER drugs, so let's get back to topic. Two thirds of this thread consists just of arguments about ER when it should be about the chemistry and pharmacology of !!!T I L I D I N E!!!
I'm tired of this tedious back and forth arguing...

P.S.: also, if OROS prevents dose dumping, doesn't that actually mean that ER does indeed work? I thought it doesn't work? I thought this whole thing is just something "political"? So how can a purely political definition achieve an actual biochemical effect and prevent defeating the mechanism that slows release?

 

[Hexenstahl]

It's kind of ironic that I told you that this is what people do & then it basically happened to you too. People trying to tell me I'm wrong about shit left & right, only to say the exact same thing I said (just slightly different) in another reply.

Yeah I'm currently getting a live demonstration of this in 4K ultra high definition quality LOL.

I have absolutely zero problems with being educated or told what's right or correct as I enjoy learning (to the best of my ability) anyway but that's not what's actually happening here. Just people needing their ego's stroked to the point where they're willing to deflect & even just make shit up

SAME!

 

[Hexenstahl]

Seriously though, let's get back to topic now. TILIDINE or death!

 

[DeathIndustrial88]

I wish I had some experience with Tilidine, which is why I've been pretty quiet in this thread.
I don't think it's even available in America, sadly. Maybe it is & just isn't used much.

From what I've read though, it's metabolite is roughly as potent as morphine. Bisnortilidine sounds like it has no analgesic activity, but I haven't read that far.

Is tilidine totally synthetic or does it fall into being an Anilidopiperidine, Phenylpiperidine, Diphenylpropylamine or a Benzomorphan?
I think I'd be able to tell this by looking at it's molecular structure (I'm pretty ignorant on chemistry stuff), but I figured I'd ask to get the conversation back on topic of tilidine. lol I'm going to guess that it's in none of these classes & probably just considered an "other synthetic" opioid. Similar to how tramadol is classed. I didn't even know tilidine existed until recently.

I'll let everyone else with more experience & knowledge about it speak. I'm full aware of when I don't know things & am not afraid to admit it.
I'm here to learn & enjoy myself.

Tilidine sounds like a very curious drug though & it'd be interesting to have a few goes with it!
I'd be curious to know too what other obscure opioids could be synthed from it.


This abstract from 1975 calls Tilidine "non-narcotic". (lol gee where have I heard that before) but seems to insinuate that a tilidine/pethidine combo has a longer duration & less respiratory depression. Which to me, makes me wonder what about tilidine would cause there to be less respiratory depression from pethidine (maybe some NRI/DRI properties?) But since it's an abstract and from 1975, it could be total BS. Doesn't offer any real science behind it either.

"The onset of action was slightly faster with pethidine, but the duration of action was longer with pethidine-tilidine combinations. Respiratory depression and sedation were less evident after pethidine-tilidine combinations than after equianalgesic doses of pethidine."

The interaction of tilidine and pethidine in postoperative pain - PubMed

The mode of interaction between the new, non-narcotic analgesic tilidine and pethidine was studied in the treatment of postoperative pain. The potency ratio 3:1 (pethidine:tilidine) found previously was used in the comparison. Thus 0.25 mg/kg of pethidine with 0.75 mg/kg of tilidine and 0.5...

pubmed.ncbi.nlm.nih.gov

I have no experience with pethidine though either. But I wouldn't mind giving this combo a try. lol

 

[emkee_reinvented]

"someguyontheinternet" apparently needs to find a life.... off the internet.

Tell me more.What happened did I miss something. Need for a life we all need and internet forums are just a part of it.

And a good excuse to give a to Hexenstahl. Its a great forum most use drugs and sometimes thread's derail. No need to use spells. Kiddin'

 

[emkee_reinvented]

Wow - well that's me told/ You know more than me after 8 weeks - impressive.

I didn't come up with the idea of SR formulations not working, it's something that is accepted industry-wide. Ask your own pharmacist.

But I can't help wondering if the Dunning-Kruger effect is in action. I, for one, wouldn't study a subject for 2 months and presume to be an expert. I've studied it for 35 years and every single day I realize that their is so much more I don't know.

I assure you I will not bother you again.

Well most dr.s, psychiater's mostly know near to nothing, despite their long studie's. If I dive in NCBI in particular looking for what happened to me. gives way better info.

So 8 week's sounds to me as enough time to gather a lot of knowledge, Enough to outwit any professional.

That said any of you actually took Tilidine and how did it feel?

 

[AlsoTapered]

The context was dose dumping in terms of consuming the pills with alcohol not that it was creating a constant plasma concentration. Dose dumping in this context is defeating a mechanism that slows release.

Also plasma concentration does not necessarily correlate with perceived effects, I don't use an extended release mitragynine extract but I perceive the same level of benefit for the entire day from one morning dose. The plasma concentration is changing over that time

Dose dumping due to alcohol was a real problem with Opana (I believe). @Skorpio states that it's hydromorphone but I don't wish to squabble. Either way it was a 12 hour formulation of a potent opioid that if taken on an empty stomach and topped up with a couple of shots (is that term understood in the US? I mean 2 fingers of Wild Turkey for example) would dissolve the polyamide excipient and result in overdose.

the true SR is a complex calculation which included the Ki of a given drug but for the last... 50+ years the plasma level has always been used (by manufacturers) to demonstrate SR formulation. Now, I guess they would presume people will use the LogP of the drug to estihttps://www.nature.com/articles/1300790mate the free concentration within the CNS but I don't think Ki is used. I'm not confident that mean receptor occupancy time has EVER been used considered although it IS a valid term. Until recently it simply wasn't possible to test but I note:

Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing - Neuropsychopharmacology

The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central μ-opioid receptor occupancy after a clinically effective dose (20 mg...

www.nature.com

It's still doesn't provide an occupancy time BUT it does note that it appears to be a dynamic value under chronic administration.

I guess it exposes what we don't know and so use a best-estimate. As for subjective effects... well, they are subjective only if you refer to a psychoactive drug. Even then, subjectivity is, well, a subjective concept. Having worked with ER doctors I know that a pain score (for example) is meaningless. Personal experience means I always qualify by saying 'well, I was in an accident in which my right hip was dislocated and much of it destroyed - so shall I can only scale by what I have experienced'.

I've noted that people who have suffered severe burns will tend to give lower pain scores because from what I hear, burns and especially chemical burns can produce levels of pain that makes suicide the only viable way out. WP burns are infamous for this.

 

[Hexenstahl]

All right, I finally have the time to answer you now.

I don't think it's even available in America, sadly.

As far as I'm aware (I could be wrong ofc) the drug Tilidine is sold only by two german pharma companies called "Aliud Pharma" and "1A Pharma GmbH" and I don't think they have FDA approval to sell this compound in the US. Perhaps they do, but only under a different brand name??? Maybe you can go to the pharmacy next time you're downtown and ask them if it's even available in your country.

From what I've read though, it's metabolite is roughly as potent as morphine.

Precisely! I think the drug also acting as a dopamine reuptake inhibitor might explain the additional euphoria of this opioid. I mean Tilidine's euphoria is something that has really burned itself deeply in my mind. It was so incredibly pronounced and hella motivating! That's what I remember the most. Tilidine was like pure opioid euphoria in a pill! No sedation at all plus a strong motivation to do things. If the prodrug only had the potency of morphine or even higher, it would be totally worth to get the drug, but with a potency of 0.1 - 0.2 PLUS the stupid naloxone they have added to the pills it's really not worth it. I'd really love to make a potentiated form of this compound if I had the skill and the legal license to do so. I'm sure it would sell incredibly well. And I'm also sure that it would probably become your fav opioid due to the motivation aspect being really pronounced with this compound.

Bisnortilidine sounds like it has no analgesic activity, but I haven't read that far.

The german wiki article about bisnortilidine states that it is a primary amine, but it seems to not have analgetic activity. However that doesn't mean it doesn't do anything potntially significant in the body/brain. Maybe it has some regulatory function or activates something for nortilidine to actually be able to do its job properly. I don't know. The article also says that citable sources regarding bisnortilidine and its effects don't exist which could mean that this metabolite hasn't been researched yet. Maybe I'll find something about it on pubchem.

Is tilidine totally synthetic or does it fall into being an Anilidopiperidine, Phenylpiperidine, Diphenylpropylamine or a Benzomorphan?

Tilidine is just like tramadol a phenylpiperidine. I have tried looking for a source to back up my claim and luckily found one (took me some time though).

Differences between opioids: pharmacological, experimental, clinical and economical perspectives

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries ...

www.ncbi.nlm.nih.gov

Scroll down to table 2 and you see that both tilidine and trams belong to the same chemical structure class.

I'd be curious to know too what other obscure opioids could be synthed from it.

Maybe one day we end up with some powerful tilidine derivative that is strong enough to be worthwhile for us who are hooked on potent opioids. My Levomethadone dose isn't even high and I'd need a shit ton of Tilidin to feel something. I'm on 33mg Levo, which is between 12 to 15 times the equivalent dose of morphine. Let's say I need 15x the amount of morph. That's 495mg in morphine. Tilidine has 0.1x the potency of morphine, so I'd need close to 5000mg or 5 freaking grams of Tilidine for it to get me high!!!
That's 25x 200mg Tilidine pills that I need to swallow lol. That's ridiculous, so yeah I'm desperately waiting for a derivative that has at least the same potency as morphine.

This abstract from 1975 calls Tilidine "non-narcotic". (lol gee where have I heard that before)

That used to be the classic marketing strategy of pharmaceutical companies back in the day to get rid of their opioids lol. Things were simple back in the day. Simply produce something addictive that didn't exist before, tell the ignorant public (and the equally ignorant doctors who can't read and interpret structural formulas and therefore not notice that it's a fucking opioid and all opioids are addictive) that it's not a narcotic and therefore non-addictive and BAM, that's how you used to do marketing and make money lol. Although I'm not too sure if that strategy is really dead. I mean even to this day some doctors here in Germany think Pregabalin is non-addictive (yeah I know it's not an opioid) and throw that shit after you like they're smarties. And pregabalin isn't an old medication. It was sold back in the 90s as non-addictive and it's sold even today and prescribed by many ignorant doctors as a non-addictive anti-convulsant and off-label anxiolytic.

 

[izo]

As far as I'm aware (I could be wrong ofc) the drug Tilidine is sold only by two german pharma companies called "Aliud Pharma" and "1A Pharma GmbH"

As said it was invented by goedecke, they also put gabapentin on the market. Aliud and 1a Pharma sell tilidine as generics. And it seems mainly an European thing. I don’t think they sell it in the USA. They stick to oxycodone and hydromorphone mainly there. Tramadol is also available of course.

Tilidine is just like tramadol a phenylpiperidine.

Tilidine could be called a phenylcyclohexeneamine whereas tramadol could be called a phenylcyclohexanol. They are rather different in its structure and the only thing that is the same with them is their potency. They also behave rather different pharmalogically.

 

[AlsoTapered]

The interesting thing is that tilidine does overlay the A-and B rings of morphine. While it is synthetic, it's binding to the same domain.

Now, nortilidine and possibly bisnortilidine are kind of interesting because they happen to overlay N-methyl cypenamine and cypenamine respectively. Both appear to have affinity for the mu opioid receptor BUT also act on the monoamine transporters.

I don't believe the original researchers ever considered that the metabolites of tilidine happened to overlay certain DRIs but I suspect than animal models produced somewhat unexpected results.

I did post a link to what, for want of a better name I refer to as isotilidine with isonortilidine and bis dinotisotilidine being active DRIs.

I don't know if you have ChemOffice but both nortilidine, bisnortildine, isonortilidine ans bis isonortilidine do, amazingly, closely overlay cypanamine. It's worth noting that while cypenamine has a primary amine and is listed as having DRI activity only 10% of that displayed by amphetamine, the lesser known N-methyl derivative is twice as potent.

In short, nortilidine and isonortilidine demonstrate the opiate activity of morphine but they also demonstrate about 20% of the activity of dexamphetamine.

So a dose of 50-100mg of nortilidine will have the opioid activity of (about) 100mg of morphine (although the tilidine metabolites have a lower MW so on a molar basis they are more potent - although affinity data isn't well established) but it's also able to produce the DRI (stimulanr) activity of 10-20mg of dexamphetamine.

BUT it's important to note that none of those compounds appear to demonstrate NRI or SRI activity.

It's a really unexpected find.

About once a year I go back to tilidine/nortilidine and isonortilidine to check if a novel synthetic step makes them facile targets. I've done this for over a decade and yet, no, no new chemistry allows a simple ynthesis.

BUT I 100% should mention that their has recently been a significant advance in the possible synthesis of isonortilidine.

Put simply, N-(2,4-dinitrophenoxy)methanamine (CAS 38100-39-9) allows an alkyl halide to be replaced with a methylsmine moiety. Now, that sounds like an AWESOME trick to make methamphetamine (for example) but it isn't cheap. It's only viable if the product is of a high value... I mean, I was REALLY pleased to find it, but it's really a niche reaction.

 

[Hexenstahl]

As said it was invented by goedecke

Hello izo. The user DeathIndustrial88 did not ask who INVENTED Tilidine, but whether or not it is SOLD in the US market. Therefore I answered that to my knowledge the only remaining manufacturers are Aliud and 1A Pharma. I think it is mainly sold in Germany but it could be that one of these firms (or both) has a subsidiary in Poland because I have seen Tilis there when I visited my polish friend a while ago.

Tilidine could be called a phenylcyclohexeneamine whereas tramadol could be called a phenylcyclohexanol.

Well, according to both the source I have provided as well as my judgement as a layman both Tilidine and Tramadol belong to the chemical structure class known as the "phenylpiperidines". Or am I misunderstanding something here?

EDIT:
no I'm sorry, I was wrong about Poland. Tilidine is sold in Luxemburg, Belgium, Bulgaria, Switzerland and some south african countries. I think my friend must have smuggled them from Germany or I'm confusing them with another opioid that had a similar pill shape.

 

[izo]

the only remaining manufacturers are Aliud and 1A Pharma

Years ago I checked and it was also available as a generic by sandoz but this was years ago.

Phenylpiperidines are coumpounds like Pethidine and the like, tramadol and tilidine have nothing in common with them.

 

[Hexenstahl]

Phenylpiperidines are coumpounds like Pethidine and the like, tramadol and tilidine have nothing in common with them

Yes Pethidine is made out of the compound 4-phenylpiperidine which is its base structure (and also of Loperamide and other drugs). Well, I'm confused now because the british pharmacological society which wrote that article I posted states in table 2 that Tilidine and Tramadol belong to the chemical structure class #2 and when I looked below what category that number is, it lists them as belonging to phenylpiperidine. It made sense to me because of how similar the Tilidine compound looks to the skeletal structure of phenylpiperidine , similar to how prodine's and pethidine's structure have similarity to phenylpiperidine.

I'd be thankful if you could elaborate a bit more so I can understand why Tilidine has nothing in common with phenylpiperidines as you say. Thank you.

 

[izo]

It made sense to me because of how similar the Tilidine compound looks to the skeletal structure of phenylpiperidine

well yes they look kinda the same when you look at them from a wider angle but neither tilidine nor tramadol contain a piperidine ring. the both contain a cyclohexane (or in case of tilidine a cyclohexene aka cyclohexane with one double bond in it) ring but piperidine is a 6 membered ring where one atom is a nitrogen:

piperidine:

cyclohexane as in tramadol:

and cyclohexene as in tilidine:

hope that helps.

 

[DeathIndustrial88]

I've had this handy guide on my computer for years (dunno why) lol I dunno how accurate it is.... But it just lists tramadol as an "other synthetic".... And of course doesn't mention tilidine, so it made me curious.

Is it possible tell what class an opioid is by looking at it's skeletal backbone? Or am I thinking of something else.
I really only have surface/entry level knowledge on this kind of stuff. But I find it interesting & like to save stuff, so I can come back to it later on when I understand it more.

1.

Phenanthrenes: morphine, codeine, heroin, hydromorphone, and oxycodone
2.

Benzomorphans: pentazocine and phenazocine
3.

Diphenylpropylamines: propoxyphene, methadone, levo-α-acetylmethadol, loperamide
4.

Phenylpiperidines: meperidine, also known as pethidine
5.

Anilidopiperidines: fentanyl, alfentanil, and sufentanil
6.

Oripavine derivatives: etorphine, dihydroetorphine, and buprenorphine
7.

Morphinan derivatives: levorphanol and butorphanol
8.

Other types of opioids: some types of synthetic opioids do not belong to the mentioned categories. One of these drugs is tramadol, a synthetic analogue of codeine (Stolberg, 2011).

 

[Hexenstahl]

well yes they look kinda the same when you look at them from a wider angle but neither tilidine nor tramadol contain a piperidine ring. the both contain a cyclohexane (or in case of tilidine a cyclohexene aka cyclohexane with one double bond in it) ring but piperidine is a 6 membered ring where one atom is a nitrogen:

piperidine:

cyclohexane as in tramadol:

and cyclohexene as in tilidine:

hope that helps.

WOW! Thanks I got it now! I was so confused there for a second lol. You know, I'm still in the middle of studying general chemistry and haven't reached organic chem yet, so I make lots and loooots of mistakes when reading skeletal structures
That's about to change though.

 

[Hexenstahl]

I've had this handy guide on my computer for years (dunno why) lol I dunno how accurate it is.... But it just lists tramadol as an "other synthetic".... And of course doesn't mention tilidine, so it made me curious.

Is it possible tell what class an opioid is by looking at it's skeletal backbone? Or am I thinking of something else.
I really only have surface/entry level knowledge on this kind of stuff. But I find it interesting & like to save stuff, so I can come back to it later on when I understand it more.

1.

Phenanthrenes: morphine, codeine, heroin, hydromorphone, and oxycodone
2.

Benzomorphans: pentazocine and phenazocine
3.

Diphenylpropylamines: propoxyphene, methadone, levo-α-acetylmethadol, loperamide
4.

Phenylpiperidines: meperidine, also known as pethidine
5.

Anilidopiperidines: fentanyl, alfentanil, and sufentanil
6.

Oripavine derivatives: etorphine, dihydroetorphine, and buprenorphine
7.

Morphinan derivatives: levorphanol and butorphanol
8.

Other types of opioids: some types of synthetic opioids do not belong to the mentioned categories. One of these drugs is tramadol, a synthetic analogue of codeine (Stolberg, 2011).

Hey that's a really handy list. The table of contents of the book "Opioid Analgesics: Chemistry and Receptors" is written in a similar way but lists the classes in a historically chronological way which I find really cool because you can see how opioid synthesis has developed over time. However I haven't read that book yet because it is way too advanced for me right now. I maybe grasp 1/6th of it lol. It's a book that costs $300 but I was lucky enough to find it on ebay for 110 bucks so I ordered it ofc. I think that book along with Opiate Receptors by Gavril Pasternak have been the best knowledge investments I have ever made so far.

 

[AlsoTapered]

That double bond is important as unlike piperidine and cyclohexane, cyclohexene cannot sit in a chair or boat conformation. The later reversed-ester homologue uses a cyclopentane ring which, surprisingly, places the benzene, O lone-pairs (from the ester) and N lone-pair in almost precisely the same relative spatial position.

I believe dihydrotilidine was actually tested and proved to be almost inactive BECAUSE neither boat nor chair conformation will provide the appropriate spatial relationship.

 

[izo]

I believe dihydrotilidine was actually tested and proved to be almost inactive BECAUSE neither boat nor chair conformation will provide the appropriate spatial relationship.

In the book by Casey/parfit it was stated that the double bond is absolutely necessary for tilidines activity.