Tianeptine - novel scaffold for an opioid?

[Fertile]

image-2022-04-19-122340360 hosted at ImgBB

Image image-2022-04-19-122340360 hosted in ImgBB

ibb.co

Literature References: Tricyclic compound with psychostimulant, anti-ulcer and anti-emetic properties. Prepn: C. Malen et al., DE 2011806 corresp to US 3758528 (1970, 1973 both to Sci. Union et Cie-Soc. Franc. Rech. Med.). Neuropharmacology study: C. Malen, J. Poignant, Experientia 28, 811 (1972).

Human MOR Ki - 194±70 nM

I am always fascinated when researchers discover a totally unexpected activity in a new medicine. The benzylamine motif is found in quite a few of the more modern opioids from ciramadol to BDPC, from the 3-henyl-3-amino-propionamide derivatives (reference already on the site) to metopholine (and homologues). But you will notice that iin every case, the benzene ring is meta or para substituted? The meta is almost always an -OH therefore the ring is phenolic therefore antagonist activity is possible.... but the para substitution is generally a halogen. I DID find reference to a ciramadol homologue in which the m-OH (aromatic a meta phenol) was swapped for a p-Cl. Sadly the paper was unavailable, but their is certainly a QSAR being built up here.

So, using that basis, the -Cl of tianeptine is para to the benzylamine motif. In this case the amine is secondary, but their are other examples of this and just about the first thing to do if searching to improve MOR Ki is to make that amine tertiary. Of course, the heptanoic acid N-substitution does make the structure the 'magic' 15 methylenes long.

Modelling depression in animals is VERY crude. We don't really understand how it manifests and so we have to derive activity from behavior. Crude AND cruel.

But does the sulfonamide appear in any other opioids? Yes it does. IC26 uses a ethylsulfonyl as bioisostere for methadone's ethyl ketone, the ethylsulfonyl analogue of ketobemidone is known. Data-miners may also note that when fentanyl was being developed, as well as the amide series, Janssen also produced a carbamate ester and a sulfonamide series (I am guessing HE had read of them being used as bioisosteres in opioids). Actually, for people who live in nations where novel RCs are still legal, the carbamate esters of the fentanyl series looks promising.

Finally there is that second aromatic (benzene) ring. It would be interesting to substitute it with, say, a thiophene or furan. There are a stack of 5-membered aromatics but I presume the chemistry of the one's I suggest makes them the logical start point. IF the 2-thienyl homologue (for example) were equipotent (or better) then it's reasonable to suspect where that would overlay fentanyl (for example).

What I THINK happened was that the designers of this medicine began with amineprtine and sought to make it less a specific dopamine releaser and rather something with a broader scope of action (or 'dirtier' as it is termed in pharma development teams). I haven't tried aminpertine but apparently there were 186 doctor's reports in France of patients who had become dependent on the stuff. for it's stimulant properties - no mention of opiate activity. It strongly suggests that the p-Cl making the compound 15 methylenes long is a KEY factor in it's MOR affinity.

But it provides a view to the sheer scope of the 6-(benzylamino)hexanoic acid motif. I suggest that the carboxylic acid moiety might have been chosen because getting such a large alkyl chain through the BBBis rather tricky. I mean, I know THC manages it, but THC is exceptional in many ways.

 

[izo]

I was totally surprised as I first saw tianeptines structure, so odd looking for an opioid. But the para chloro fits only good to especially tianeptines structure. I had w-15 (Canadian paper I believe) with a para chloro substitution which was totally rubbish. It felt just wrong (meaning the 4-Cl substitution), a 3oh or plain phenyl would have fitted much better to the rest of w-15.

I think tianeptine is very special case as an opioid and I have no suggestions how to alter it or compare it to other opioids.

 

[Fertile]

Well, BDPC has a p-Br, The p-Cl homologues of quite a few phenolic opioids are available, so I presume they are active.

Didn't that w series turn out not to be opioids?

Since even Dan Lednicer could not explain why the p-Br & p-Me were so much more active, even with the simpler dimetamine series, I suspect it's quite complex. Obviously it adds steric bulk but I think that the para group influences electron density in the ring and increase affinity and maybe the electronic character of the -Cl comes into play.

I don't THINK anyone has tried it with 35Cl or 37Cl even though it has now been shown that it DOES make a difference. I think lithium was the first drug in which it was shown. It turned out that 6Li is much more active than 7Li. I've seen a blood-pressure medication that had a methyl ether and when the CH3-O- was swapped for a CD3-O-, the body couldn't metabolize it as fast.... but it's quite a new field of investigation.

But if nothing else, the length from the -Cl to the -OH of the carboxylic acid is 15 methylenes. I keep finding that in every series of potent opioid, the most potent homologue is 15 methylenes. I mean from fentanyl to etonitezine to BDPC to the sec-heptyl analogue of (dihydro)etorphine.

I mean, the affinity isn't very good BUT maybe the tertiary amine (add an N-methyl?) will be better? They were not searching for such activity but I haven't read all of the patents yet. It's going to need a lot of mining but I am often amazed that researchers are unaware of what other researchers have done (until the information age, anyway). Wasn't dimethylaminopivalophenone discovered twice.... also, look at dimethylaminopivalophenone and then those 3-phenyl-3-amino propanamide opioid I referenced last month. Seem familiar?

 

[izo]

The W compounds are opioids, but w-15 is quite weak and was one of my least favorite opioids I tried. Were they invented by knaus? idk from the top of my head. What I wanted to say with my w-15 example is that a para chloro isn’t favored for compounds which fit the classic opioid rule, eg methadone or morphine. For atypical compounds like etonitazene, bdpc or tianeptine para substitution clearly works but I think you cannot compare all of these different templates. (Eg para ethoxy the most potent sub for the etonitazene like compounds, who would have thought of this).

 

[Fertile]

Fentanyl-related designer drugs W-18 and W-15 lack appreciable opioid activity in vitro and in vivo

W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist ...

www.ncbi.nlm.nih.gov

So, unless it has some indirect action like preventing the body from metabolizing endorphins, it doesn't seem to have such activity. There were many hits on the search, I just referenced this one because it's not strident, Someone just quietly did the work.

I did see a lot of stuff written about it and you will note that the paper is from 2017 and so the myth was around for a long time.

The p-Cl homologue of faxeladol is another example (commercially available) and I guess so is bromadoline.

I did find a few 'lesser spotted' opioids from patents and I'm sure that there are many more. The problem is that the search terms are difficult to find. From the 1970s their Ki was usually measured against naloxone so one could search for that, but before then they are difficult to pin down. I quickly realized that almost every major lab had produced at least ONE candidate and so I was able to use that.

Of course, with Janssen it's the problem of finding them ALL. I mean, some of them are so well buried and the most recent ones are so vague and encompass such a huge number of compounds without any hint of the most active. Usually one has to just presume Example 1 is at least a reasonable example but even that isn't always true. In that paper you provided, looking back at the Janssen patent, it was examples 32,34 & 35 (if memory serves) that were the really potent ones.

 

[izo]

Can’t argue with that but w-15 had clearly weak activity at the mu receptor…

 

[Fertile]

The LogP of W-15 suggests it won't cross the BBB so I guess that in vitro it ay have activity, but possibly not in vivo.

Believe me, I was just as disappointed. It would have been REALLY useful as part as a training set. BUT cepradapranol is certainly useful.

But tianeptine IS active, seemingly. The tertiary sulfonamide offers hydrogen bond acceptor, something else to consider. It kind of has all of the bits and pieces one expects to see, but sulfur atoms are RARE. apart from the ethylsulfonyl being a bioisostere of an ethylketone moiety. I THINK I've posted an image of a sulfinyk in a phenylpropyl chain. It was reported to be very potent but that is the only one I have seen.

I'm almost certain that much of the observed antidepressant activity is due to it's opioid activity, so maybe it's the most potent of the series?

 

[arrall]

Fascinating compound, though I question how sustainable it is to use MOR agonists as antidepressants in the long-term.

 

[Fertile]

I couldn't comment on it's opiate activity. It's affinity is NOT high but I'm not sure of it's LogP at physiological pH. It's provided in the form of the sodium salt but if that carboxylic acid is free, the LogP will be much higher.

I am just keen to extract as much information as possible from this compound. I am getting tired of data mining patents. I DO keep finding more and more examples of overlooked opioids (such as those based on benzapines) but it seems like designers are STILL discovering new compounds through rational design based on insight - it's an area in which each team carefully guards their own insights.

I do believe that the dimethylaminopivalophenone represents the prototype for an entire new class of highly potent ligands. Just as pethidine lead to phenoperidine led to fentanyl. Just as methadone lead to ORLAAM (levomethadyl acetate) led to R-4066 (note the latter is 15 methylenes long), there is a lot of potential. I suspect it's overlooked because by the time it was discovered (Russia 1959, USA 1964) phenoperidine was in use & ORLAAM was in development - nobody wanted to do the BASIC research involved in a new scaffold.

 

[Xorkoth]

It is for 100% sure an opioid, and in high doses it is quite euphoric, though short lasting. It also causes opioid withdrawal upon cessation if used long enough to develop dependence.

 

[izo]

Btw, when it comes to analogs, I heard that the ethyl ester and the iodo derivatives have been sold. Can anybody with experience of these make a comparison to tianeptine?

 

[Fertile]

Ester where? Iodo where?

 

[izo]

Ester at the end of the carbon chain where the COOH group is and the iodo as a substitution for the chloro. Never saw any analog of tianeptine offered, only read from it here at bluelight. It was @negrogesic i believe.