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N&PD Moderators: Skorpio | thegreenhand
⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club
- Thread starter nuke
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Feretile
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Many thanks. It was compound 10 that was in the paper I saw. I'm tired now, but I will read it properly tomorrow. It does closely match up with the Janssen patent and the later patent I cited. It is well worth reading both patents with this paper in front of you.
Feretile
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OK, I'm begging again:
https://doi.org/10.1021/acs.joc.8b01673
Direct N-H/N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents
Just so people realise, I AM aware that the quality of many papers of Indian origin are very dubious. Anyone else remember the fake '1-pot synthesis of fentanyl' that was someone's pHd work (and got retracted since it was made up) BUT:
1)This is published in the JOC, a high impact journal.
2)The researchers have worked on several papers on aziridines so it seems they have developed a knowledge bade.
3)They cite and are cited appropriately and not just other people within their own department (a la Jan Hendrik Schön AKA Nobel Scandal)
4)A totally different team developed a related approach (N-phenoxy) while they use an animoxy
So why the hassle?
OK, so you likely wonder what the heck is the point of THAT? Well, it's because that 3-membered ring is under a lot of strain and so it will ring-open to an alkanolamine or an aminoester or an aminoketone or an aminoalkylsulfonate or... well MANY things. What is even better is that the ring-opening will be almost 100% trans. I mean 99.8% ee or better (i.e. >99.9% trans)
Now, if one were to apply it to say (a ring-substituted) propenylbenzene, you could produce optically pure (ring-substituted) pseudoephedrine. I just use those as examples. I do not see any advantage in that since IF you wanted those, it's only of great benefit when the precursors are costly.
BTW the catalyst for THIS reaction is Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]. The catalyst costs £400/gram so you can see it's only when the precursor is EXPENSIVE. It is actually a very interesting example of how a catalyst works. When you get that far down the periodic table, you can get some wacky oxidation states. Rh can be +1, +2, +3, +4, +5, +6 and the catalyst has a LOT of steric bulk and so it works by promoting an electron (HOMO/LUMO theory).
It get's VERY complex. I am hoping that their will be alternatives BUT I need the article to test.
https://doi.org/10.1021/acs.joc.8b01673
Direct N-H/N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents
Just so people realise, I AM aware that the quality of many papers of Indian origin are very dubious. Anyone else remember the fake '1-pot synthesis of fentanyl' that was someone's pHd work (and got retracted since it was made up) BUT:
1)This is published in the JOC, a high impact journal.
2)The researchers have worked on several papers on aziridines so it seems they have developed a knowledge bade.
3)They cite and are cited appropriately and not just other people within their own department (a la Jan Hendrik Schön AKA Nobel Scandal)
4)A totally different team developed a related approach (N-phenoxy) while they use an animoxy
So why the hassle?
OK, so you likely wonder what the heck is the point of THAT? Well, it's because that 3-membered ring is under a lot of strain and so it will ring-open to an alkanolamine or an aminoester or an aminoketone or an aminoalkylsulfonate or... well MANY things. What is even better is that the ring-opening will be almost 100% trans. I mean 99.8% ee or better (i.e. >99.9% trans)
Now, if one were to apply it to say (a ring-substituted) propenylbenzene, you could produce optically pure (ring-substituted) pseudoephedrine. I just use those as examples. I do not see any advantage in that since IF you wanted those, it's only of great benefit when the precursors are costly.
BTW the catalyst for THIS reaction is Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]. The catalyst costs £400/gram so you can see it's only when the precursor is EXPENSIVE. It is actually a very interesting example of how a catalyst works. When you get that far down the periodic table, you can get some wacky oxidation states. Rh can be +1, +2, +3, +4, +5, +6 and the catalyst has a LOT of steric bulk and so it works by promoting an electron (HOMO/LUMO theory).
It get's VERY complex. I am hoping that their will be alternatives BUT I need the article to test.
Last edited:
S.J.B.
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The product of this reaction will be racemic. There is no source of enantioinduction, as the catalyst is achiral. The classic way to perform the asymmetric aziridination is with copper and a chiral bisoxazoline ligand. Evans, in fact, performed the aziridination of propenylbenzene in the original paper. It only gave 70% ee, but enrichment via recrystallization should be viable.OK, I'm begging again:
https://doi.org/10.1021/acs.joc.8b01673
Direct N-H/N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents
Just so people realise, I AM aware that the quality of many papers of Indian origin are very dubious. Anyone else remember the fake '1-pot synthesis of fentanyl' that was someone's pHd work (and got retracted since it was made up) BUT:
1)This is published in the JOC, a high impact journal.
2)The researchers have worked on several papers on aziridines so it seems they have developed a knowledge bade.
3)They cite and are cited appropriately and not just other people within their own department (a la Jan Hendrik Schön AKA Nobel Scandal)
4)A totally different team developed a related approach (N-phenoxy) while they use an animoxy
So why the hassle?
OK, so you likely wonder what the heck is the point of THAT? Well, it's because that 3-membered ring is under a lot of strain and so it will ring-open to an alkanolamine or an aminoester or an aminoketone or an aminoalkylsulfonate or... well MANY things. What is even better is that the ring-opening will be almost 100% trans. I mean 99.8% ee or better (i.e. >99.9% trans)
Now, if one were to apply it to say (a ring-substituted) propenylbenzene, you could produce optically pure (ring-substituted) pseudoephedrine. I just use those as examples. I do not see any advantage in that since IF you wanted those, it's only of great benefit when the precursors are costly.
BTW the catalyst for THIS reaction is Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]. The catalyst costs £400/gram so you can see it's only when the precursor is EXPENSIVE. It is actually a very interesting example of how a catalyst works. When you get that far down the periodic table, you can get some wacky oxidation states. Rh can be +1, +2, +3, +4, +5, +6 and the catalyst has a LOT of steric bulk and so it works by promoting an electron (HOMO/LUMO theory).
It get's VERY complex. I am hoping that their will be alternatives BUT I need the article to test.
Feretile
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I think I said that ring-opening produces the trans pair. In fact I very clearly said it produced the trans pair. I think I clearly stated that it was the intention. It's the ring-opening that is key - BOTH trans diastereomers are active.
In addition, I did (and I admit I only) infer that BARE aziridines was a very important element of this step. There are quite a lot of papers on the production of protected aziridines but that would entirely defeat the object - making the N-triflate, deprotecting and then N-alkylating... is no saving.
If I were prepared to go via 3 steps I would just go via the aminohalide & then condense out the haloacid which is very well documented and has been around for over 50+ years. and is as cheap as dirt. It's the cost of the precursor that is the key here... which I did mention.
Of course it is certainly useful to have more reference. One can never have too much reference. So I must thank you for that... after all, you did far more than anyone else. If I am being a little vague as to the product, it's because it's a product that few know of and I certainly would not want to see the price & availability of the already costly precursor to shoot up. I'm sure you can appreciate that if suppliers SEE a suddenly profitable precursor, they will hike that price.
In addition, I did (and I admit I only) infer that BARE aziridines was a very important element of this step. There are quite a lot of papers on the production of protected aziridines but that would entirely defeat the object - making the N-triflate, deprotecting and then N-alkylating... is no saving.
If I were prepared to go via 3 steps I would just go via the aminohalide & then condense out the haloacid which is very well documented and has been around for over 50+ years. and is as cheap as dirt. It's the cost of the precursor that is the key here... which I did mention.
Of course it is certainly useful to have more reference. One can never have too much reference. So I must thank you for that... after all, you did far more than anyone else. If I am being a little vague as to the product, it's because it's a product that few know of and I certainly would not want to see the price & availability of the already costly precursor to shoot up. I'm sure you can appreciate that if suppliers SEE a suddenly profitable precursor, they will hike that price.
Feretile
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I am on the beg for (I hope) the last time. Some years ago I found a paper which discussed the QSAR of a series of novel kappa agonists. Well, as you may know, the difference between mu & kappa ligands is that the latter has an extra methylene spacer. Someone put the kappa patent on Scribd, but since I wasn't totally up on kappa ligands, I wasn't SURE I could modify to make a mu ligand.
Well, the team behind the kappa ligands have released a paper on the mu ligands of the same class.
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands
The lead compound is thus:
Now, it only has 4 of the 5 key moieties and it's only 14 methylenes in length. Now, the opbious solution would be to lengthen the 1-phenylethyl moiety to a 1-phenylpropyl BUT that introduces and extra rotatable carbon bond and I assume that this LOWERS potency. From notes, a 3-cinnamyl chain the middle carbon-bind is olefinic i.e. -CH=CH- but this then placed the beta benzene ring in the wrong position.
As it is, the compound cotains 4 of the 5 key moieties and I am willing to bet that borrowing a trick from BDPC, a p-Br is added to the alpha benzene thus:
There examples with a m-OH (phenol) on the alpha benzene ring but these a mixed agonist/antagonists but since this compound closely overlays BDPC, ad p-Br seems likely. It was Lednicer who identified the optimum biosteric minumum for mu agonists - 15.
There are related compounds like ciramadol but the m-OH yields mixed agonist/antagonist activity. I could never find the paper but their is a ciiramadol homologue which replaces mixed activity with pure mu agonist. In that case, replacing the m-OH with a p-Cl has been made and tested and is a stimulating opioids. I dare say that the 3,4-dichlori derivative will be even more potent.
There are still more opioids that have been lost to the depths of time I intend to visit the Bodlian with a massive number of references to hunt down.
While I have said all of this, I also deeply interested in GMO. GMO opium poppies, GMO cannabis (lots of HC but none for the stuff that causes severe side-effects.
My last aim is to provide VERY safe opioids and to write a book on the subject. Pyrazolam was chosen because it can be made in 3 steps.... and the immediate precursors is available. OK I will also seek to improve on pyeyzolam (by adding a second benzo thar produced effects almost indistinguishable from ethano....
But their is always room for research.
Oh, and look out for etofixine or more likely an etofixine derivative - while not EXACTLY like alcohol, it's really nice, really safe and water soluble so it can be put into drinks (and I do not mean spiking.
I could go on and and on but I see people are bored.
But I am always keen for people to ask questions not found in an educational system.
The payoff> I know a few people whose mental health has been destroyed with LSD and I feel that we should do more to help.
S.J.B.
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Monitoring methamphetamine in the United States: A two-decade review as seen by the DEA methamphetamine profiling program
Corresponding author: Steven Toske (Special Testing and Research Laboratory, U.S. Drug Enforcement Administration, Dulles, U.S.A.)
Drug Testing and Analysis 2022, Volume 14, Issue 3, Pages 416–426
Published online October 27th, 2021
Corresponding author: Steven Toske (Special Testing and Research Laboratory, U.S. Drug Enforcement Administration, Dulles, U.S.A.)
Drug Testing and Analysis 2022, Volume 14, Issue 3, Pages 416–426
Published online October 27th, 2021
https://doi.org/10.1002/dta.3186
Feretile
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Some years ago I happened upon a new class of kappa ligands. As people may know, in many cases (such as U-47700) the difference between a kappa ligand and a mu ligand is a single methylene spacer. I've spent AGES looking for the paper with no luck.... but bless me, if I did not find the mu homologue of the compound, to whit:
2,2-dimethyl-3-(methylamino)-3-phenyl-N-(2-phenylethyl)propanamide
As those who have read my paper on mu agonists, you will see 4 of the 5 key moieties and a biosteric minimum. I suggest that a p-Br (like BDPC) on the alpha benzene (closer to the amine) would increase potency as the compound is 14 methylenes long, not 15. The researchers did make the m-OH and made the alkyl chain an extra carbon long, but antagonist it was. The above is, to the best of my knowledge, an agonist.
Bioorganic & Medicinal Chemistry Letters
Martin P. Allen, James F.Blake, Dianne K.Bryce, Mary E. Haggan, Spiros Liras, Stafford McLean & Barb E.Segelstein
https://doi.org/10.1016/S0960-894X(00)00034-2
Received 1 October 1999, Accepted 4 January 2000, Available online 8 March 2000.
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands
Steely eyed viewers may suggest that an -OH on the benzylic carbon of the beta aromatic MAY increase affinity. Then of course the mystery of why the active compounds are ALL secondary amines suggests that the secondaries are the more potent. The compound is also 14 methylene's in length and so their is an argument to add a p-Br (or p-Me) to the alpha benzene (the one closer to the amine moiety.
I do not think we can expect massive activity, but maybe 60x M is not unreasonable.
Oh, and on a point of secondary amines. the -CH3 of the amines forms a hydrogen-bond with the =O so you consider there to be an extra rung.
2,2-dimethyl-3-(methylamino)-3-phenyl-N-(2-phenylethyl)propanamide
As those who have read my paper on mu agonists, you will see 4 of the 5 key moieties and a biosteric minimum. I suggest that a p-Br (like BDPC) on the alpha benzene (closer to the amine) would increase potency as the compound is 14 methylenes long, not 15. The researchers did make the m-OH and made the alkyl chain an extra carbon long, but antagonist it was. The above is, to the best of my knowledge, an agonist.
Bioorganic & Medicinal Chemistry Letters
Martin P. Allen, James F.Blake, Dianne K.Bryce, Mary E. Haggan, Spiros Liras, Stafford McLean & Barb E.Segelstein
https://doi.org/10.1016/S0960-894X(00)00034-2
Received 1 October 1999, Accepted 4 January 2000, Available online 8 March 2000.
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands
Steely eyed viewers may suggest that an -OH on the benzylic carbon of the beta aromatic MAY increase affinity. Then of course the mystery of why the active compounds are ALL secondary amines suggests that the secondaries are the more potent. The compound is also 14 methylene's in length and so their is an argument to add a p-Br (or p-Me) to the alpha benzene (the one closer to the amine moiety.
I do not think we can expect massive activity, but maybe 60x M is not unreasonable.
Oh, and on a point of secondary amines. the -CH3 of the amines forms a hydrogen-bond with the =O so you consider there to be an extra rung.
Feretile
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Some years ago I happened upon a new class of kappa ligands. As people may know, in many cases (such as U-47700) the difference between a kappa ligand and a mu ligand is a single methylene spacer. I've spent AGES looking for the paper with no luck.... but bless me, if I did not find the mu homologue of the compound, to whit:
2,2-dimethyl-3-(methylamino)-3-phenyl-N-(2-phenylethyl)propanamide
As those who have read my paper on mu agonists, you will see 4 of the 5 key moieties and a biosteric minimum. I suggest that a p-Br (like BDPC) on the alpha benzene (closer to the amine) would increase potency as the compound is 14 methylenes long, not 15. The researchers did make the m-OH and made the alkyl chain an extra carbon long, but antagonist it was. The above is, to the best of my knowledge, an agonist.
Bioorganic & Medicinal Chemistry Letters
Martin P. Allen, James F.Blake, Dianne K.Bryce, Mary E. Haggan, Spiros Liras, Stafford McLean & Barb E.Segelstein
https://doi.org/10.1016/S0960-894X(00)00034-2
Received 1 October 1999, Accepted 4 January 2000, Available online 8 March 2000.
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands
Steely eyed viewers may suggest that an -OH on the benzylic carbon of the beta aromatic MAY increase affinity. Then of course the mystery of why the active compounds are ALL secondary amines suggests that the secondaries are the more potent. The compound is also 14 methylene's in length and so their is an argument to add a p-Br (or p-Me) to the alpha benzene (the one closer to the amine moiety.
I do not think we can expect massive activity, but maybe 60x M is not unreasonable.
Oh, and on a point of secondary amines. the -CH3 of the amines forms a hydrogen-bond with the =O so you consider there to be an extra ring thus:
PS I would be just as keen to read about the antagonists (one's with meta -OH) and the kappa homologues (with extra methylene spacer.
2,2-dimethyl-3-(methylamino)-3-phenyl-N-(2-phenylethyl)propanamide
As those who have read my paper on mu agonists, you will see 4 of the 5 key moieties and a biosteric minimum. I suggest that a p-Br (like BDPC) on the alpha benzene (closer to the amine) would increase potency as the compound is 14 methylenes long, not 15. The researchers did make the m-OH and made the alkyl chain an extra carbon long, but antagonist it was. The above is, to the best of my knowledge, an agonist.
Bioorganic & Medicinal Chemistry Letters
Martin P. Allen, James F.Blake, Dianne K.Bryce, Mary E. Haggan, Spiros Liras, Stafford McLean & Barb E.Segelstein
https://doi.org/10.1016/S0960-894X(00)00034-2
Received 1 October 1999, Accepted 4 January 2000, Available online 8 March 2000.
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands
Steely eyed viewers may suggest that an -OH on the benzylic carbon of the beta aromatic MAY increase affinity. Then of course the mystery of why the active compounds are ALL secondary amines suggests that the secondaries are the more potent. The compound is also 14 methylene's in length and so their is an argument to add a p-Br (or p-Me) to the alpha benzene (the one closer to the amine moiety.
I do not think we can expect massive activity, but maybe 60x M is not unreasonable.
Oh, and on a point of secondary amines. the -CH3 of the amines forms a hydrogen-bond with the =O so you consider there to be an extra ring thus:
PS I would be just as keen to read about the antagonists (one's with meta -OH) and the kappa homologues (with extra methylene spacer.
Fertile
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Can anyone obtain:
"Analgetics. II. Relationship between structure and activity of some beta-amino ketones". Journal of Medicinal Chemistry. 12 (6): 994–7. doi:10.1021/jm00306a006. PMID 5351480
I am interested to know if dimethylaminopivalophenone can undergo an alteration in N-substitution to make a diampromide analogue. OK so the result is only ≈M in potency BUT other aromatics increase potency as does a benzylic -OH.
It won't set the world on fire, but it's an unknown area of QSAR.
"Analgetics. II. Relationship between structure and activity of some beta-amino ketones". Journal of Medicinal Chemistry. 12 (6): 994–7. doi:10.1021/jm00306a006. PMID 5351480
I am interested to know if dimethylaminopivalophenone can undergo an alteration in N-substitution to make a diampromide analogue. OK so the result is only ≈M in potency BUT other aromatics increase potency as does a benzylic -OH.
It won't set the world on fire, but it's an unknown area of QSAR.
Fertile
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Has anyone else used:
Apparently it's supposed to get past paywalls by pretending to be a web crawler (as used by search engine I presume).
I haven't had a lot of luck, but if someone can work out how to use it, it sounds a clever if time limited (I can see how one would defeat it while still allowing crawl).
Apparently it's supposed to get past paywalls by pretending to be a web crawler (as used by search engine I presume).
I haven't had a lot of luck, but if someone can work out how to use it, it sounds a clever if time limited (I can see how one would defeat it while still allowing crawl).
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I tried this to access a pay walled recipie on bon appetit and it worked albeit with a little bit of deformatting.
Great resource though, thanks for the tip!
lonelyDude
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could not find this here.
its on the genetic testing of patients to see if there cyp2d6 enzymes are active and dosages of codeine based on such tests.
pubmed.ncbi.nlm.nih.gov
its on the genetic testing of patients to see if there cyp2d6 enzymes are active and dosages of codeine based on such tests.
Codeine Therapy and CYP2D6 Genotype - PubMed
Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics. Codeine has also been prescribed to prevent coughing, though the antitussive administration is most often in liquid formulations and in conjunction with other medications. (1, 2) The...
pubmed.ncbi.nlm.nih.gov
Fertile
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izo
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Fertile
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I think the server https://doi.org/10.1002/ejoc.201200308 glitched. I now have the paper. So what has it taught me? I need 2 more even more obscure papers?
A Review on Synthetic Approaches towards Kavalactones - DOI 10.1055/s-0040-1706044
Stereoselective Heck Reaction of Allylic Esters with Arenediazonium Salts DOI 10.1055/s-0029-1218126
I'm quite prepared to do the heavy lifting, if I have the references. As you can see, obscure!
A Review on Synthetic Approaches towards Kavalactones - DOI 10.1055/s-0040-1706044
Stereoselective Heck Reaction of Allylic Esters with Arenediazonium Salts DOI 10.1055/s-0029-1218126
I'm quite prepared to do the heavy lifting, if I have the references. As you can see, obscure!
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Molecular recognition of morphine and fentanyl by the human μ-opioid receptor
This paper is pretty badass. It maps different opioids ability to recruit beta arrestin at the mu opioid receptor, and determines the regions of the protein required for that interaction. Finally they make a few fentanyl analogs that do not couple to beta arrestin.While this isn't a definative answer to the question whether beta arrestin is responsible for the negative effects of opioids, the protein level determination and development of new compounds will allow this to be probed accurately in living systems.
Molecular recognition of morphine and fentanyl by the human μ-opioid receptor
Seeing how fentanyl, morphine, and other agonists bind and activate the μOR-Gi complex provides the basis for designing ligands with reduced arrestin signaling.
www.cell.com
izo
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2000 - GABA-Activated Ligand Gated Ion Channels Medicinal Chemistry and molecular Biology
pubmed.ncbi.nlm.nih.gov
good paper, although a bit older a good review.
GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology - PubMed
GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology
pubmed.ncbi.nlm.nih.gov
good paper, although a bit older a good review.
Fertile
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It's interesting that 4-phenylphenapromide (equally 4-phenylpropiram) overlay fentanyl PREFECTLY. Synthesis means they do not represent decent targets but they do overlay. So I presume bioisosteres of said phenyl will also wotk. If you place an -OH at the tertiary carbon adjacent to that 4-phenyl, you get an achiral compound as potent as beta-hydroxy fentanyl.
I forget how potent beta-hydroxy fentanyl is, but the compound I mention is x150M.
Anyone care to guess if their is an alkyl substitution of the piperidine ring that is like 3-methyl fentanyl? You see, whereas 3MF gives 4 enantiomers, this class would just give 2 isomers...
So totally guessing I think it's possible to get about x600M. More if you replace propanamide with other, more modern amides.
I forget how potent beta-hydroxy fentanyl is, but the compound I mention is x150M.
Anyone care to guess if their is an alkyl substitution of the piperidine ring that is like 3-methyl fentanyl? You see, whereas 3MF gives 4 enantiomers, this class would just give 2 isomers...
So totally guessing I think it's possible to get about x600M. More if you replace propanamide with other, more modern amides.