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Drug designs. (MedicinalUser SAR thread)

The SAR data for phenoperidine is here:
J., Paul A; Eddy, Nathan B. (1960). "Compounds Related to Pethidine--IV. New General Chemical Methods of Increasing the Analgesic Activity of Pethidine". Journal of Medicinal and Pharmaceutical Chemistry. 2 (1): 31–45. ISSN 0095-9065. doi:10.1021/jm50008a003.

Also some patents thrown in for good measure:
[1] Pohland Albert, US2951080 (1960 to Eli Lilly and Co); CA, 55, 4540c
[2] Jr Frank A Cutler & James F Fisher, US2962501 (1960 to Merck and Co Inc).

According to the Janssen article it says phenoperidine is 99 (mouse) & 219 & 186 (rat) times the potency of pethdine.

Pheneridine was listed as 35 and 13 times pethidine (mouse).
 
Other analogs to help compile SAR narrative:

Remember the novelty of the idea lies in its attempt to build SNDRI/opioid activity conflated into a single design.

I'm not interested in NK1/SRI activity.
 
^Shao's design was ditto albeit cyclohexyl (instead of piperidine)

These are the IC'50s for the 3',4'-Dichloro: 5-HT = 19nM NE=4nM DA=1nM

For beta-Naphthyl the following SAR data is garnered: 5-HT =<1nM NE=7nM DA=3nM
 
As I see it, the inherent problem of trying to design multiple and diverse activities into a single compound is effective dose - especially when people respond differently to different doses of each.

I hate to break it to you - but what's the advantage of this over, say, a conventional triple-reuptake inhibitor and a conventional opioid.

If it's purely an academic exercise which you never intend to actually make, that's fine.

But if you want to actually MAKE stuff, it could be a lot of money wasted.
 
I only thought of the idea today while I was doodling in chemdraw and realized the similarity in the structures between New Orleans and Sunovion/Sepracor then realized that hybrids are possible based on the two compounds. I felt the urge to share my findings but have not had time yet to fully digest the information.

I didn't actually say i was planning on making the above compounds yet. I did shelve the idea as a possible avenue for future drug discovery though.

Companies/universities waste money all the time for "research" of new compounds. I don't know how much of what is written in the journals/patents actually ends up in the clinic but I am guessing that it is less than 1% of the time, and yet they probably feel as if they are still contributing something useful into the discussion.

I actually had the same idea as you that having a group of SNDRI's and a group of opioids as separate compounds might work more satisfactorily than trying to conflate both activities into a single target. (I did it mostly to demonstrate if any such relationship between SNDRI's and opioids does exist and that I am not just copying other chemists inventions when I mix the separate ideas together to come up with a completely novel target that was never made before.) But come to think of it, compounds such as 3',4'-Dichlorotramadol also exist and may already employ this "hybridization" approach to SNDRI's/opioids. In the case of tramadol and tapentadol it worked out successfully on a commerical scale so it did not turn out to be a wasted endeavor to produce such agents. Albeit, these were only SNRI/NRI opioids and not fully blown SNDRI opioids.

I am able to produce a patent by Neurosearch where they do it though.

The compound in question is called Trifluorofentanyl.
US20110046180 idem Dan Peters, et al. WO2009077584 (2011 to NeuroSearch AS).
However, their adventure did not appear to be that successful, although a relatively strong mu-opioid, data in the SNDRI department was only micromolar.
 
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MedicinalUser247 said:
I'm hypothesizing a new Phenethylamine design called DioxolaneMethamphetamine. Dioxolane is a heterocyclic acetal. It is related to tetrahydrofuran by replacement of the Methylene group at the 2-position with an oxygen atom. Sense it's chemical structure looks similar to Methylene dioxy it could in possibility be just as psychoactive. How ever this has not been tested. In theory it would just be as active as MDMA. This hypothesis is just based on comparing molecules, but just because of that it doesn't mean they would have the same effect. But it could prove to be a new form of MDMA. Basically because of it's similarity with the replacement of the Methylene group. So, what are your thoughts on this ?
Click to expand...
It's In PiHKAL And Is Called EDMA. As Far As The Commentary Went, Shulgin Wrote, "There Is No Reason For EDMA To Make Sense."

1-(1,4-dioxatetraline-6-yl)-2-methylaminopropane.png


EDMA
1-(1,4-dioxatetraline-6-yl)-2-methylaminopropane

This Is What You Are Referring To, Yes?
 
Smyth2 said:
Companies/universities waste money all the time for "research" of new compounds.
Click to expand...

When it comes to medicines, nobody 'wastes' money. It's the nature of drug discovery that roughly 99.99% of all compounds will never find their way into medicine.

TBH like you I apply rational design. Sadly, most researchers no longer do - HTS is the way it's going. Now that IS wasteful because you might make the same compound 100 times but unless you test for the sought activity, you don't realize it's active at all.
 
The sidechain idea is better illustrated for the MPPP analogs R1317 & R1480 (for which there is a wikipedia entry).

I recall that the idea explored in the clinic by Sepracor/Sunovion for the sibutramine analogs was called SEP-432.

but this was a SNRI active in humans at 300mg/day which is a long shot from the highly potent SNDRIs exemplified above.

[1] Sramek, John J.; Hardy, Larry W.; Bieck, Peter; Zamora, Cynthia; Versavel, Mark; Kharidia, Jahnavi; Grinnell, Todd; Chen, Yu-Luan; Sullivan, Michael; Ding, Hong; Cutler, Neal R. (2016). "Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects". CNS Neuroscience & Therapeutics. 22 (5): 404–412. doi:10.1111/cns.12513. ISSN 1755-5930.
[2] Liming Shao, et al. US9868718 (2018 to Sunovion Pharmaceuticals Inc).

You are right to state that it is a waste of money to start developing such a complicated novel medicine if not being thought about for purely academic reasons. It probably ranks on a 1-5 difficulty rating as in the same league as something like Osanetant, for example. That is why I don't need to keep the logic private since no one could just steal these ideas because it is not that practical to do. (Even if the idea appears practical in a fully equiped professional laboratory, you would still have to pay for it so none of it is completely freely had.)

One thing I was thinking about last night is the name. A lot of the novel compounds I designed in my cloud I managed to assign codenames to based on their structure or inventors. For example, 3,4-Dichlorotramadol I codenamed Slimadol (based on Liming Shao's name). I was also able to come up with the pet names Brasoperidine and Tesoperidine for the meperidine analogs I listed above (based on brasofensine and tesofensine).
 
I have a simple rule that for a target to be facile, synthesis must be three decent yielding steps or fewer. It seems I'm not the only one to think this way. Look at all of the RCs and you will find it's a small minority that take more than three steps. Beyond that, the assets required go up steeply.

So in your case, I would find the appropriately substituted 1-alkylaryl-4-piperidone. You may counter by saying 'but those are obviously controlled' which is an interesting point. Since you honestly intend to use it to make something legal, you can order with impunity. In the UK, you need to register your business and obtain a licence but since you aren't actually making anything illegal, why would that concern you? We did!

It didn't take me long to figure out that the availability and price of key precursors made me choose one compound over another.

Often, what ISN'T a controlled precursor can be a surprise. Mixed anhydrides and their diyl derivatives spring to mind. Of the latter, their is an almost inexhaustible supply and even the former offers dozens of options.

Often, what's commercially available is also often a surprise. We made a sample of G-130 via the dehydration of what I believe was a topical treatment for muscular pain, Fepradinol (2-[(2-hydroxy-2-phenylethyl)amino]-2-methylpropan-1-ol). If memory serves, the suppliers were so used to selling it in large quantities that when we asked for a sample (officially for instrumental analysis), they sent it gratis!

I think I can mention the above since it turned out not to be orally active and we were not about to offer something that required parenteral administration. But it trained me to see what seemingly unrelated compounds could be used for.
 
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Making G-130 starting from Fepradinol sounds as easy as you are ever going to get. I hadn't realized Fepradinol is commerically available though.

Enefexine
4-(4-Ethylphenyl)piperidine
Fb: [67765-04-2]

CH634298 idem Georges Haas, Alberto Rossi, Pier G. Ferrini, Oswald Schier, US4188396 (1980 to Ciba-Geigy Corporation).

For Ex 1 in the (Swiss) patent (Ex 17 in the US patent) they hydrolyze the nitrile to the acid and then decarboxylate the acid.

This procedure could work with the 3',4'-dichloromeperidine precursor too (c.f. MIN-117).

It's probably easier to start from the 4-piperidone though as here:

4-(naphth-1-yl)piperidine
[130305-64-5]
Daniel James Koch & Vincent Patrick Rocco, US6303627 (2001 to Eli Lilly and Co Ltd (GB)).

These simpler compounds reminds me of an agent I have in my database called:
4-(4-chlorophenyl)-1-methylpiperidine
[776-89-6]
[1] E. Peel Mervyn, et al. CA827682 (1969 to Allen and Hanburys Ltd).
[2] J. Harper Norman, et al. CA827154 (1969 to Allen and Hanburys Ltd).
[3] David Jack, et al. US3458521 (1969 to Allen and Hanburys Ltd).

Narcotic agent that is more potent than codeine but less potent than morphine for relieving pain. Additionally, antidepressant and mild appetite suppressant properties.
 
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Hey 3DQSAR, i understand you're concerns that some of the above reading appears academic and not that practicably feasible.

I like you thought of novel ideas based on 4-piperidone. Without having to invent anything new I can show you an existing idea I already discovered (I posted it in the novel opioid thread but am reposting it here):

I call this one Haldolgesic
4-(4-Chlorophenyl)-1-(1-phenylethyl)-4-piperidinol
[63959-34-2]

Link patent:
Toshiaki Kumazawa, et al. WO1997010213 (to Kyowa Hakko Kogyo Co Ltd, US Department of Navy).

Source matter:
Leysen, Josee, Jan P. Tollenaere, Michel H.J. Koch, and Pierre Laduron. “Differentiation of Opiate and Neuroleptic Receptor Binding in Rat Brain.” European Journal of Pharmacology 43, no. 3 (June 1977): 253–67. https://doi.org/10.1016/0014-2999(77)90025-5.
 
It's rare to see a bear hydroxyl BUT we know from other classes that it's the ⭕ that is responsible for binding.

Do they deal with the two isomers seperately?
 
^They don't discuss the two isomers separately.

If you want another easy stimulant similar to G-130 may I suggest the following benzazepine:

1-Phenyl-2,3,4,5-tetrahydro-3-benzazepine
Fb: [20390-68-5] (R)-: [89253-81-6]

Lewis A Walter & Wei K Chang, US3393192 (1968 to Merck Sharp and Dohme Corp).
Anon., CH555831 (1974-11-15 to Scherico Ltd.).

These compounds work on dopamine receptors although I can't find bioactivity data for the plain phenyl rings specifically.

If you stick stuff on the phenyl rings you end up with Trepipam, SKF-83,959 etc...

But for the plain phenyl group all that is needed is b-PEA + styrene oxide, then ring form by dehydration in acid.

SKF-38,393 is a synthetic compound of the benzazepine chemical class which acts as a selective D1/D5 receptor partial agonist.
It has stimulant and anorectic effects.

[1] Castañer, J., Hillier, K. (1980). "SKF-38,393". Drugs of the Future. 5 (10): 507. doi:10.1358/dof.1980.005.10.61936.
[2] Carl Kaiser, et al. GB1561305 (1977 to SmithKline Beecham Corp).
[3] Kaiser, Carl; Dandridge, Penelope A.; Garvey, Eleanor; Hahn, Richard A.; Sarau, Henry M.; Setler, Paulette E.; Bass, Lawrence S.; Clardy, Jon (1982). "Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine". Journal of Medicinal Chemistry 25 (6): 697–703. doi:10.1021/jm00348a017.
 
It is in one of the associated papers. Ir REALLY surprised me and you have to admit, not something I would make up because it seems so counterintuitive. Only the Swiss would go to the lengths of even testing the different isomers in what is, after all, an initial round of research.

The benzapine reminds me of an antidepressant that was briefly used an an anoretic. In that case it was withdrawn due to side-effects. If memory serves the benzapine had a 3-chloro moiety - but I freely admit I only saw it years ago.

In that 'novel opioids' thread there is a benzapine. It isn't very potent but the N substitution pattern is unusual. They even tested oral activity which shows that Shetty's team was serious about it being a medicine.

I just liked the fact that G-130 could be made for pennies. From a topical cream of all things!

Now I haven't sampled it but I'm told that amfonelic acid is VERY similar to cocaine BUT it's also an antibiotic so I expect if one were to present it as such, it would go unnoticed. In fact, I knew one Dutch lunatic who bought oxalinic acid (sold to put in fish tanks as an antibiotic) and worked up the dose!!! Crazy guy. There IS a paper in which oxalinic acid's stimulant activity was compared to amphetamine in animal models. Much less potent but the Dutch guy said it was actually more like MDMA.

Now I like unusual stuff, but I draw the line at consuming fish medicines.

But here is the thing - you can buy order oxalinic acid quite legally AS an aquatic antibiotic... so could related compounds likewise be sold?
 
I tried contacting Chinese suppliers several months ago and amfonelic acid, although available, was a high price:

US$120/g CPT your office by Fedex on 25g
Quality: white powder, 98%min, pls see attached NMR for reference
Packing: 25g /bag
Lead time: around 6 weeks after yr P.O confirmed

Not tried inquiring into Oxolinic acid. Maybe that could be worth taking a look at the price?
 

'Fish medicine' grade is really cheap. But for gods sake, don't eat fish medicines!!! I just meant that if one were to market amfonelic acid as another aquarium antibiotic, would the PSA actually cover it? Who knows.

If you seek a synthetic that has a similar action to cocaine, clofenciclan is, apparently, the best one. Again, just what I hear. It was intended as a symptomatic treatment of Parkinsons disease. Now a little nugget I stored in 1988 was from the BBC Horizon programme 'The Case of the Frozen Addicts' which deals with the fallout of badly made MPPP but it mentions one Barry Kidston - the first one-off victim. He developed Parkisons-like symptoms after taking homemade MPPP but the detail left out was that he began to abuse whatever drug he was given to treat the symptoms (it wasn't specified). Eventually his doctors changed his medication and within a week he was found dead after injecting some ungodly amount of cocaine.

So my GUESS is that he was being given some sort of dopamine releaser. It's rather hard to find out what medicines were being used 48 years ago in another nation. However, it may well have been a dopamine releaser. Given that his illness was so unique, I can see specialists trying unusual medications.

ibb.co

26-Barry-Kidston-1 hosted at ImgBB

Image 26-Barry-Kidston-1 hosted in ImgBB
ibb.co ibb.co
 
MedicinalUser247 said:
I'm hypothesizing a new Phenethylamine design called DioxolaneMethamphetamine. Dioxolane is a heterocyclic acetal. It is related to tetrahydrofuran by replacement of the Methylene group at the 2-position with an oxygen atom. Sense it's chemical structure looks similar to Methylene dioxy it could in possibility be just as psychoactive. How ever this has not been tested. In theory it would just be as active as MDMA. This hypothesis is just based on comparing molecules, but just because of that it doesn't mean they would have the same effect. But it could prove to be a new form of MDMA. Basically because of it's similarity with the replacement of the Methylene group. So, what are your thoughts on this ?
Click to expand...
So because it shares characteristics with an active agent you assume activity? Dioxolane is a bulky addition, that and those oxygen will affect overall charge and binding affinity, assuming its even a ligand.
 
aftershocknrock said:
So because it shares characteristics with an active agent you assume activity? Dioxolane is a bulky addition, that and those oxygen will affect overall charge and binding affinity, assuming its even a ligand.
Click to expand...

DiFMDA, EDA and IDA all appear to be significantly less potent than MDA.


It was insightful of a researcher to swap the 3,4-MD benzene system with a 6-benzofuran aromatic as it dealt with several issues at once:

1-It indicated if the rings being planer increase activity
2-It allowed the QSAR to be expanded
3-It avoided legal complications for researchers looking into entactogens.

If memory serves, the benzofurans were patented in 1999.

As Shulgin noted, the 3,4-MD ring produced almost unique activity. I did briefly wonder why nobody had tried a benzoxathiolyl ring but now I note someone IS offering 1-(1,3-benzoxathiol-5-yl)propan-2-amine (MY200) but I cannot find any research on it.
 
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