Novel Opioids

[paracelsius]

Library Genesis

libgen.rocks

Library Genesis

libgen.rocks

Hotlink to papers.

I also note that the N-phenylethyl derivative is also known BUT I suspect that the LogP is too high. Now, IF that turned out to be the issue, then the 2-hydroxy-2-phenylethyl, 2-(2-thienyl)ethyl) or even the 2-hydroxy-2-(2-thienyl)ethyl MIGHT solve the problem. If so, I would fully expect them to have a potency in the range of x35000-x45000M (conformation permitting).

But is it a facile target? I suspect not. So fascinating and well worth knowing for when one is seeking to design a training set, but I know of much simpler compounds (1 step synthesis) that proved not to be practical because the precursors were too costly, even if their potency was some x500 M.

The Chinese pursued that one from the Japanese work the N-phenethyl with a meta-hydroxyphenyl

analgesia about 500M in rabbits, 1200x rats. binds so tightly to mu (~2000x guinea pig ileum and 6600M in mice vase deferens) the chinese thought it is "irreversible" as it can hardly get washed off by ohmefentanyl still 80% bound after 2 wash!!..ohmefentanyl FFS!!! now that is superpotent but I dont believe it is irreversible!, just picomolar potent!The logP is not really big issue (~ similar to fent). Onset of analgesia IV rats iirc is like 2-3min, duration 2x that of M so lipophilicity not affecting much else Tmax will be large (at least in the brain).. I found those quite interesting especially the one without the meta-hydroxy (reasonable 5xM). anyway am more into stim than opioids SAR. that one (parent anazocine) got my attention: It is BOTH stimulant and opioid. Come to think about it, no big surprise: they're basically like meperidine/ketobemidone with a propano bridge so behave similar (they NDRI+MOR).

No, synth is straightforward (grignard + ketoazabicyclane get the carbinol then boil HCL/MeOH) (cf the original JPN paper. Azabicyclanone is dirt cheap, else if one want play around with analogs, then can easily made via Robinson Actually
strange some fine chem companies are selling it COC1(C2CCCC1CN(C2)CCC3=CC=CC=C3)C4=CC(=CC=C4)O ! CAS 92836-37-8. Am not aware of any "research" use as MOR ligand . there are tons of them...

Jin et al. P-7521 - A New Irreversible Opioid Ligand. Acta Pharmacologica Sinica Vol 10, No 3 (May 1989) Free access

Abstract​

In the receptor binding assay, P-7521 was a potent opioid ligand which acted mainly on mu receptor. The relative affinity ratio at mu, delta and kappa sites was 66:8:1. The inhibitory effects of P-7521 were 1868 and 6060 times more potent than morphine on the electrically evoked contractions in guinea pig ileum and mouse vas deferens, respectively and were readily antagonized by naloxone and Mr2266. These results indicate that P-7521 acted on mu receptor in guinea pig ileum and mouse vas deferens. In rabbit vas deferens, the compound had no agonist activity, but could antagonize the inhibitory effect of U-50488 H, a kappa agonist, showing the antagonistic characterization was on kappa receptor. The dissociation of P-7521 binding to opioid receptor were very difficult in mu binding assay and bioassays

Analgesic activity and respiratory inhibition of 3-(β-phenylethyl)- 9β-methoxy- 9α- (m-hydroxyphenyI)-3-azabicyclo)-3-3azabicyclo[3,3, 1]-nonane (P-7521 ) in rabbits - Zhou - Acta Pharmacologica Sinica Vol 8, No 1 (January 1987) ABSTRACT
7521 is an azabicycloalkane derivative. When P-7521 was given iv to rabbits, its analgesic ED50 was 0.37μg/kg, the analgesic activity was 427 times as potent as that of morphine, and the duration of analgesic action was double that of morphine. The analgesic dose depressed the respiration slightly. But when doses even as large as 1200×ED50 were given, the respiratory action was never completely depressed, asphyxia and death were not encountered

Free access First paper in Chinese w/english abstract table, data..etc... Good'day All BLIghters Stay Safe Out There

 

[AlsoTapered]

Affinity ≠ efficacy.

I didn't add those two to the long list of hotlinks I've added to the 'useful links' thread because it isn't a facile target. But it isn't included in either off the books I hotlinked to but it does fit perfectly to the 'relative spatial position of key moieties' thing I posted.

There are many, many more but if they were factice and novel, I wouldn't post them. So while Z-4349 is interesting, I don't see it flooding the streets. It's chiral N-substitution has never been tried on another scaffold and seems to offer an interesting way of placing the N lone-pair into it's agonist or antagonist conformation.

 

[AlsoTapered]

BTW also take a look at tilidine and more specifically nortilidine and it's reversed ester (patent for reversed ester mentioned in Wiki tilidine page.

The nor compounds are also monoamine reuptake inhibitors (see similarity to cypenamine).

 

[paracelsius]

I always wonder if anybody has tried bioiosteric replacement of (nor)tilidine carboxylic ester ---> ethanesulfonyl ala sulfo-ketobemidone. EtSO2 or MeSO2pretty good CO2Et replacement with added bonus of longer T1/2. then again, iirc with methadone, the sulfonyl homolog is bunk (10x less active). ketbemidone I dont know but would be very interesting...

 

[AlsoTapered]

No, the ethanesulfonyl is merely variable. In some it was as potent as methadone, in others only half as potent. The ethanesulfonyl analogue of ketobemidone was just as potent in animal models... but it's a pain to make.

I think an ester or reversed-ester is required. IF a meta-OH were added to the scaffold, maybe the ketone would work....

But as it is, nortilidine and isonortilidine are a total nightmare to make. I don't mean the optical resolution - that's not hard. But making them at all.

Pity because nortilidine is uniquely euphoric. The trans pair is mu agonist, NMDA antagonist & monoamine transport inhibitor.

Library Genesis

libgen.rocks

 

[AlsoTapered]

Library Genesis

libgen.rocks

The above link states that nortilidine is a mu agonist/NMDA antagonist and dopamine reuptake inhibitor BUT the article refences:

Brayfifield A. Tilidine hydrochloride. The complete drug reference. Martindale: Pharmaceutical Press, 2013.

No page number - so I haven't been able to check. If someone else can, that would be great.

It makes sense since cypenamine is a stimulant ¼ the potency of amphetamine that overlays isonortilidine. If like amphetamine ---> methamphetamine an N-methyl doubles the potency then it's easy to understand the DRI activity. Energy minimized overlay of isonortilidine & morphine show how the A-ring overlays the aromatic, the ester overlays the B-ring and the nitrogen lone-pairs overlay almost perfectly. That it's the secondary amine that is active is of interest.

 

[AlsoTapered]

The Chinese pursued that one from the Japanese work the N-phenethyl with a meta-hydroxyphenyl

analgesia about 500M in rabbits, 1200x rats. binds so tightly to mu (~2000x guinea pig ileum and 6600M in mice vase deferens) the chinese thought it is "irreversible" as it can hardly get washed off by ohmefentanyl still 80% bound after 2 wash!!..ohmefentanyl FFS!!! now that is superpotent but I dont believe it is irreversible!, just picomolar potent!The logP is not really big issue (~ similar to fent). Onset of analgesia IV rats iirc is like 2-3min, duration 2x that of M so lipophilicity not affecting much else Tmax will be large (at least in the brain).. I found those quite interesting especially the one without the meta-hydroxy (reasonable 5xM). anyway am more into stim than opioids SAR. that one (parent anazocine) got my attention: It is BOTH stimulant and opioid. Come to think about it, no big surprise: they're basically like meperidine/ketobemidone with a propano bridge so behave similar (they NDRI+MOR).

No, synth is straightforward (grignard + ketoazabicyclane get the carbinol then boil HCL/MeOH) (cf the original JPN paper. Azabicyclanone is dirt cheap, else if one want play around with analogs, then can easily made via Robinson Actually
strange some fine chem companies are selling it COC1(C2CCCC1CN(C2)CCC3=CC=CC=C3)C4=CC(=CC=C4)O ! CAS 92836-37-8. Am not aware of any "research" use as MOR ligand . there are tons of them...




Free access First paper in Chinese w/english abstract table, data..etc... Good'day All BLIghters Stay Safe Out There

I cannot see an explicit antagonist such as N-allyl or N-methylcyclopropyl. So I'm almost certain that IF it's affinity is in the pM range, it's displaying mixed activity. I have seen a couple of other classes (such as the BDPC homologue with a m-OH) in which affinity didn't translate in to activity as a full agonist would expect. THIS might be a case in which borrowing the p-Br f BPDC would prove the most active?

But no WAY is it a useful target and from what I understand it, as you increase potency, so the RANGE of potency becomes more and more variable. I mean, carfentanil DID make it to market and even though it's supposed to have a huge TI, it still proved to be as dangerous as nerve gas.

It's the SUBJECTIVE effects that are important. That is why notrilidine, isonortilidine and a few others are of more interest. I mean, a compound with mu agonism, NMDA antagonism and DRI activity is uniquely euphoric. Having tried things like Palfium, I also recognize that the dynamic change of subjective effect is key to euphoria so the activity curve is important.

 

[AlsoTapered]

N-Phenethyl-alpha,alpha-dimethyl-beta-(methylamino)benzenepropanamide

N-Phenethyl-alpha,alpha-dimethyl-beta-(methylamino)benzenepropanamide | C20H26N2O | CID 10358054 - 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

An interesting class. I've used the basic scaffold but try the chiral dimethylamine and m-OH derivatives. A mu affinity of 0.1 is pretty impressive and they didn't test the p-Br, p-Cl or p-Me which I suggest will be even more potent.

 

[Rectify]

OPIE
1-dimethylamino-2-methyl-3-(3,4-methylenedioxyphenyl)-4-oxo-5-oxacyclohexane

PENGUIN
1-diethylamino-2-methyl-3-phenyl-4-oxo-5-oxacyclohexane

 

[AlsoTapered]

I've posted a nice index paper with the 3dQSAR of mu, delta and kappa opioid ligands. It usefully contains a large training set and although not an absolute, the 'morphine rule' is a very useful starting point for designing mu ligands - and chirality IS important so one can immediately state that the above represent 8 enantiomers - and 7 are most certain to be inactive... best not to add chiral centres unless you have reason to add them.

BTW that no lactone has shown opioid activity QUITE strongly suggests that the active conformation of an ester is indeed the MINIMUM energy conformation. That is borne out in the index papers I have posted - everyone is free to read them. Ignorance is never an issue, wanton ignorance IS. That's why we go for REFERENCES.

 

[Rectify]

Since these 2 compounds are novel, of course you would want to make all 8 in one batch stereoisomers of each so that each can be chromatographed and individually tested. Thus, the way I drew the chemical--with the stereochemistry not chirally indicated--is correct for the first batch.

Your assertion that only 1 in 8 of the
stereoisomers is active is pure conjecture and may or may not be true. (As conjectures are wont to be.) Reading up on the related opioid, Nucenta (tapentadol), its makers actually only market the (R,R) chemical, even though it is reportedly the least active of the lot.

 

[AlsoTapered]

Indeed - but on this thread, we generally provide REFRENCE. The lead compound above your post IS in LibChem and I have previously given reference to people who post here. Also, the 'morphine rule' as I mentioned is the most basic set of rules that will identify almost all opioids and thus is VERY useful in weeding out random rubbish such as you have posted.

1)Aromatic System (RA)
2)Quaternary Carbon
3)2 carbon chain
4)Tertiary amine (PI)

Obviously their are many exceptions, but it does hold true for over 95% of mu ligands.

We are discussing that which is known (with reference), how we can seek to expand upon what is known (with reference) and ideally how this conforms or alters that known 3d QSAR from the index papers.

⫸STICKY⫷ - Useful neuroscience/pharmacology threads

Neuroanatomy and the Brain Erowid/BlueLight Neuropharmacology Text List of FREE Chemistry Databases BEST Websites to Self-Educate Psycho-Pharmacology?? The Big & Bangin' Miscellaneous Chemistry/Pharmacology Odds N' Ends Thread: Part 3 (see also: v. 1 & v. 2)

bluelight.org

Please read the above thread - especially the first post from May 9th which had already been PMed to others discussing the subject but which is now available to all. The Journal of Molecular Modelling paper allied to the morphine rule is actually a very good way to predict mu ligands.

And as we have discussed, the RA (ring aromatic) might not need to be a ring but rather a group that displays pi bonding which explains why allylprodine, The N-allyl derivative of U-47700 (which is touched on in the patent) and some other compounds display unexpectedly high affinity. So novel in that it explains binding. Also, since I knew the head of Upjohn's drug design team, I have quite a bit of inside knowledge on the class.

It most certainly isn't a complete list because hydrogen-bond donation isn't covered.

So while people are at livery to post novel compounds - they have to show how how it's key moieties overlay those of the paper. The paper once again used a training-set to identify key moieties and thus a link to free software to generate training sets was provides.

It's worth noting that while a lactam MIGHT seem like a novel alternative to an ester, the KEY think about the esters & ketones seen in most opioids is that spatially they place a hydrogen-bond acceptor at a distance from the ring-aromatic (the A ring).

So by all means post, but please explain why you concluded that the compound would be active. This isn't a thread devoted to randomly drawing things and declaring them to be active. You don't seem to have a clue and it's not like others haven't gone to some lengths to provide you with reference.

If you have a degree in chemistry, I'm sure you will realize the value of reference and how one has to provide a hypotheses of why a compound is active - it's not for us to prove you wrong, it's for you to prove your statements right.

 

[Delmonte421]

weeding out random rubbish such as you have posted.

Oh shit

ideally how this conforms or alters thats known in 3d QSAR

This is done by communicational chemists?

U-47700 (which is touched on in the patent)

You really love this compound, you have mentioned it several times. Would you personally use it? Is it applicable to your situation and medical interactions?

If you have a degree in chemistry, I'm sure you will realize the value of reference and how one has to provide a hypotheses of why a compound is active - it's not for us to prove you wrong, it's for you to prove your statements right.

Its a great chance to learn and understand. Just have to come with an open mind and not be any and do the research. But in his defense just because you have a degree in chemistry does not mean you actually are a chemist. Sorry but I have worked with tons of people who may have a degree and a piece of paper saying your this and that but I wouldn't trust some to purify my solvents via a distillation let alone run a lithium hydride reduction reaction and blow up the fucking lab.

 

[AlsoTapered]

I've added a LOT of reference. Someone with access to a VERY powerful UNIX based system could run a training set using hundreds or even thousands of mu ligands. Of course, one need to have decent affinity data.

U-47700 is interesting because it actually overlays beta prodine. Doesn't look like it in 2D but if you overlay in ChemOffice, it's an exact match which is why I can be reasonably confident in replacing the N-methyl of the amide (which overlays the 3-methyl of prodine) with an allyl moiety. It's just a scaffold that overlays a VERY common scaffold and allows one to investigate the QSAR of one and see if it can be applied to the other. Example 13 of the U4 patent is evidence of the N-allyl being so active.

Indeed chemistry is like being taught HOW to read (or in this case, how to use reference) and medicinal chemistry is applying that education to a much narrower field.

I mean, I'm still reading papers on tianeptine homologues to discover the pharmoaore.

 

[Delmonte421]

Its always nice to START with a retro synthesis and that can help guide you and how you can actually preform the synthesis, forward lol. Not sure if you learn about retro synthesis in undergrad but you sure as hell use it a lot in graduate, research... at least I did cause I was building my knowledge of reactions. It crazy how fast you learn reactions when you realize you cant do certain things you thought you could in your retro.
This isn't directed at you @AlsoTapered obviously

 

[AlsoTapered]

Oh, retrosynthetic strategy was something I caught onto before it was formally taught. I mean, if you read a lot of reference, you often wonder WHY the authors would start with a sometimes unexpected precursor but then you would see the yields and obviously consider how simple the workups were and so it just seemed... well, like a good strategy for want of a better term.

Although we were generally limited to 3-4 steps, convergent synthesis is an obvious method to keep the overall yield up. With Viminol analogues, it's well worth producing (2R)-N-[(2R)-butan-2-yl]butan-2-amine which as you can imagine isn't hard and conveniently isn't suspicious (so you can farm it out) but finding the most efficient route IS interesting.

As you know, any advance in any scientific subject is based on previous science. I think dihydrocodeine, hydrocodone and oxycodone were the first opioids (I would suggest that diamorphine is more of a prodrug) and pethidine was the first totally synthetic opioid but Eisleb made a LOT of compounds and screened them all because their was simply no information on the QSAR and so he produced one and eventually it lead to identification of key moieties and methadone and related 3,3-diphenyl heptanones were the first opioids that used rational design.

But the references I provide along with some of the more recent opioids show that we still do not have ALL they key moieties and I think their are 6 (which may be all of them) for mu.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

The above image doesn't include the b-ring (aromatic) which is detailed in the second reference I provided on 5th May. I mean, it's hard to think of a potent mu ligand that doesn't have 2 RAa some distance apart. Things like methadone, lefetamine, MT-45 and so forth have both of those closely positioned RAs but even R-4066 (a methadone derivative) has a 3rd and things like fentanyl and bezitramide have a second and it's THAT RA it would be nice to nail down... so that's 5 key moieties. I think the allyl (which has pi bonds) is substituting for a RA and is valuable when the addition of a full RA would push the LogP up too much.

 

[AlsoTapered]

Library Genesis

libgen.rocks

I found the above in an issue of 'Annual Report in Medicinal Chemistry'. Note that compounds 13 & 14 had an ED50 of 0.2mg/Kg which makes them significantly more potent than metofoline. What they do not seem to have tested is the p-NO2 homologue. Maybe their is a good reason for this, but I believe studies were halted because it caused cataracts in animal models.

Hard to know why such an unusual side-effect turned up nor if it would prove to be a problem in man but it's an interesting thought that their MAY be a homologue that is possibly 30-60x M in man. I don't know if the isomers were resolved and moreover if the side-effect was tested in the chiral compound but if nothing else, it DOES provide for a novel compound to be used in training sets.

The p-NO2 moiety is seen in several other chemically unrelated classes of opioid and so it's not a novel feature.

The original patent:

https://patentimages.storage.googleapis.com/a7/b8/cc/b539051dac929c/US5952344.pdf

It seems that researchers went on to search for NMDA activity so one also has to ask if the analgesia displayed WAS due to opiate activity since I can find no evidence of optical resolution. Metofoline analogues DID turn up as RCs briefly but while the synthesis for a compound x2.5M might not have made it attractive, a compound potentially x30-x60 morphine would surely make it of more interest.

 

[AlsoTapered]

BTW anyone looking closely at the above will recognize that the above is yet another example of an opioid with a benzylamine moiety, it's just that it's part of an N-methyl piperidine ring.

Once again, the (R) enantiomer is responsible for it's activity.

 

[Delmonte421]

Library Genesis

libgen.rocks

I found the above in an issue of 'Annual Report in Medicinal Chemistry'. Note that compounds 13 & 14 had an ED50 of 0.2mg/Kg which makes them significantly more potent than metofoline. What they do not seem to have tested is the p-NO2 homologue. Maybe their is a good reason for this, but I believe studies were halted because it caused cataracts in animal models.

Hard to know why such an unusual side-effect turned up nor if it would prove to be a problem in man but it's an interesting thought that their MAY be a homologue that is possibly 30-60x M in man. I don't know if the isomers were resolved and moreover if the side-effect was tested in the chiral compound but if nothing else, it DOES provide for a novel compound to be used in training sets.

The p-NO2 moiety is seen in several other chemically unrelated classes of opioid and so it's not a novel feature.

The original patent:

https://patentimages.storage.googleapis.com/a7/b8/cc/b539051dac929c/US5952344.pdf

It seems that researchers went on to search for NMDA activity so one also has to ask if the analgesia displayed WAS due to opiate activity since I can find no evidence of optical resolution. Metofoline analogues DID turn up as RCs briefly but while the synthesis for a compound x2.5M might not have made it attractive, a compound potentially x30-x60 morphine would surely make it of more interest.

what would part of the molecule would cause cataracts? Thats such a strange side effect. If its doing that in pre-clinical studies then it will never make it to market let alone should it be safer then then the zenes going around.

Metofoline was also shown to produce cataracts in dogs when they got to that phase of studies but they still marketed this drug in the early 1960's. The liver produced a compound that caused the catarats?

Did they ever isolate the stereoisomers and maybe R vs S would be the cause of the cataracts? or my little knowledge in med chem is showing and that would have no biological effect?

 

[AntiNociception]

But here is the thing - I cannot find the N-2-(2-furanyl)-ethyl moiety in any morphinan with an epoxy bridge. Maybe it's just because the more complex (fully synthetic) compounds above were made a decade or more later than the semi-synthetic examples with the bridge.... or maybe the furanyl doesn't work if the bridge is present.

The team led by B. Pelmont at H. La Roche that formed in 1949 to investigate the 14(R)-morphinans (incl. norlevorphanol derivs such as Ro4-1539 or furethylnormorphinan) were tasked with the tetracyclic "Grewe morphinans." Grewe's newfangled Bronsted-catalyzed morphinan cyclization was 'fresh-off-the-press.' the german pharma firms of this era, still partially under Allied control, who were doing a thorough job of gutting them of 'intellectual property war loot,' allowed for a brief window of time where Swiss firms were best equipped to investigate these new fully synthetic morphinans. The 4,5-epoxy bridged pentacycles had been thoroughly investigated by the earlier American NRC (later the COPDD) investigation from 1929-1941 (the key figures involved in this NRC effort were Lyndon F Small, Nathan B. Eddy, & Everette L. May). The NRC research elucidated the epoxymorphinan class w/ the hopes of finding analgesics with reduced physical dependence capacity (PDC). after investigating hundreds of compounds, they found only two candidates: metopon and desomorphine. According to NB Eddy (writing in his posthumously published memoirs "The National Research Council involvement in the opiate problem, 1928-1971") the two derivs were the only novel pentacyclic morphinans which demonstrated a statistically relevant separation of analgesia from dependence liability.

Janssen & Leysen confirmed in a pair of separate review articles, another was a chapter (can't recall the volume it was a part of, will update later when i search thru my notes) that N-phenethyl-nordesomorphine (approx 80 x morphine as analgesic) substituted equally well as N-(2-thienylethyl)-nordesomorphine when tested in SDS assays in animal subjects (morphine w/d suppression) -- both of the N-arylethyl derivs fully substituting for morphine in the SDS (morphine-habituated rodents).

I was frustrated by this reference, as it provides an analgesic estimate for the N-phenethyl deriv, but fails to mention any such analgesic estimate for the thienylethyl. Nor does it provide the mg/kg suppression dose for the the N-thienylethyl (or provide a citation whose full-text was electronically accessible at the time (it was over ten yrs ago, so perhaps they've digitized the publication) -->

quantitative comparison of the non-phenyl 2-arylethyl subsitututed N-nor-epoxymorphinans remains elusive. But I'm positive they are out there. I would check the work performed by Schmidhammer (spellling?) et al. he specializes in 14-hydroxymorphinans and the 6-keto derivs (morphin-6-ones) but he is among the few still conducting research in N-phenethyl epoxymorphinans. See "phenomorphone" or N-phenethyl-noroxymorphone

Another very interesting area of inquiry is that of the levorphanol 14(S)-epimers, so called 'isomorphinans' (M. Gates first elucidated and provided bioactivity data on the isolevorphanol series in a JACS article in 1958)

See the link below for detailed discussion of lewis acid-catalyzed cyclization of a novel 1-benzyloctahydroisoquinoline (OHiQ; an isomer of the common morphinan precursor octabase) with a shifted double bound, which, upon exposure to AlBr3 (lewis acid) cyclized to the corresponding 14(S)-isomorphinan -- the 14(S)-epimer of 14(R)-levorphanol configured morphinans



Some very unique stereochemistry, increased activity, and some fascinating work done by Marshall Gates (the same Gates who elucidated the formal synthesis of morphine in 1952).

14(S)-isomorphinans are accessible by a 'Grewe-analogous' cyclization mechanism initiated by heating with Lewis Acids (instead of the bronsted acid/H3PO4 in the conventional Grewe procedure). See the diagram below for additional insight involving cyclization of an appropriate substituted OHiQ with AlBr3



According to a 1964 article by Fry & May, the same type of benzomorphan epimer (beta-metazocine derivs) was achieved using AlCl3 -- Gates chose AlBr3 for his isolevorphanol and isocyclorphan syntheses (the specific isomorphinans that were the topic of his mechanism postulates) b/c of a recommendation by a colleague who he gives credit to in the text of his review (will have to look that one up in the actual print lit. as well--another reference not avail electronically)


Sincerely,

--Deandra

(aka: Oxycosmopolitan)

X.com/DuchessVonD

https://reddit.com/user/jtjdp