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Daniel Lednicer

haribo1

haribo1

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Daniel Lednicer discovered a series of opiates, the strongert with an ED of 0.0001mg/kg (so, 3MF style). The only problem with these pain-killers is that the take 20 minutes to kick in. For those who know the structure, there is a bare hydroxyl ehich might slow down passage therough the BBB. He mentions forming the formyl ester but no reasons why... Do you think it's to speed up the action?

Oh, and one other thing, they specifically bind to the OLR1 sub-receptor class and don't seem to produce tolerence. Isn't that amzing! That would mean that abusers (and I'm sure it will make the street, 3MF, beta hydtoxy F did) would never increase the dose to get high. Down goes the profit of the dealers. I mean, forget MMT, if this stuff is long-lived enought, then it could be a great treatment, Once someone develops partial agonists of the stuff (and they are getting there) then maybe body-chemistry can be altered back painlessly. A nalmefene inplant (and in Australia they have developed a 12 month inplant) would surely increase the revocery rate...
 
There are MANY opioid class analgesics that are very sound at not producing tolerance that exist in the research. That they have not been explored more vigorously is both surprising and a real shame...

Anyway, when you say 20 minutes you mean via IV?...if he proposed a simply formyl ester why did he not bother to test it as it is esy enough...?

all the compounds in this class are full agonists?
 
From the papers I have read, yes, full mu agonist. I can only asscribe it's slow onset to slow BBB crossing or the required conformation. Methadone, for instance, stretches the dimethyl amine back to the diphenyl system in it's active form...
 
i do not see why it being a full agonist would be in any way negative and surprisingly as you stated it is a class that as is is not producing marked tolerance
 
i do not see why it being a full agonist would be in any way negative and surprisingly as you stated it is a class that as is is not producing marked tolerance
 
ah, that's what i already assumed in the other thread (the strechting of the aryl-alkyl-moiety), but i didn't know that this is also the case in methadone.
quite interesting!
maybe that's also the reason why the "phenylethyl"-opiates like tilidine and in some way also morphine are possible (despite the fact, that opiates usually are said to require a phenylpropyl-structure).

@haribo: do you know which circumstance causes the strechting of methadone?

@smyth: besides, i'm still interested in the structural attributes of the most active one in this class of opiates, so i'd be happy if you could post it or pm it to me :) . i say that because the old thread got closed.
 
US Patent 7,183,436 example 5 is where it's at... and yes, 20 minutes for IV so orally (assuming it's orally active) then it's more like 1 hour.
I read that etonitazine turned up in Moscow where it was smoked. That stuff apparently kicks in like smack, has a higher TI and is more euphoric...
 
Like I already said, bluelight does not permit the simple upolading and exhange of articles.
That last thread got closed for a reason - PM me your email if you want to read the original files.
 
this seemed interesting and I assume this class likely also works via this mode as well:

Novel Receptor Mechanisms for Heroin and Morphine-6-Glucuronide Analgesia
NIDA grantee Dr. Gavril W. Pasternak of Sloan-Kettering Memorial Cancer Center and Cornell University Medical College and his research team have obtained evidence, using a number of different paradigms, indicating that heroin actions are most likely not mediated through the same receptors as morphine. This finding is echoed by Dr. James M. Fujimoto's observations (another NIDA grantee) that morphine, 6-monoacetylmorphine (6-MAM) (both are active metabolites of heroin), and heroin are found to exhibit unique receptor selectivities at both spinal and supra-spinal levels as well as in different mouse strains.

The rapid metabolism of heroin to 6-MAM and its slower conversion to morphine has led many to believe that heroin and morphine act through the same receptors and that the differences between them are due to their pharmacokinetics. Dr. Pasternak and his team now present evidence strongly implying that heroin and two potent drugs, fentanyl and etonitazine, act through a unique receptor mechanism similar to morphine-6-glucuronide which is readily distinguished from morphine. Heroin, 6-MAM and morphine-6-glucuronide show no cross tolerance to morphine in a daily administration paradigm, implying distinct receptors. Strain differences also reveal differences among the drugs. CXBK mice, which are insensitive to morphine, retain their sensitivity to heroin, 6-MAM, morphine-6-glucuronide, fentanyl and etonitazine. Antisense mapping of the opioid receptor MOR-1 reveals that oligodeoxynucleotide probes against exon 2, which are inactive against morphine analgesia, block morphine-6-glucuronide, heroin, fentanyl and etonitazine analgesia. Finally, an antisense probe targeting Gi1 blocks both heroin and morphine-6-glucuronide, but not morphine analgesia. These results indicate that heroin, 6-MAM, fentanyl and etonitazine all can produce analgesia through a novel analgesic system which is similar to that activated by morphine-6-glucuronide. Rossi, G.C., Brown, G.P., Leventhal, L., Yang, K. and Pasternak, G.W. Neuroscience Letter, 216: pp.1-4, 1996.
 
n,n-dimethyl-n-(4-benzyl-4-hydroxy-1-(4-bromophenyl)-cyclohexyl-)-amine.
hope that's the correct name of one of those compounds :)
 
We are strictly avoiding sources & synthesis, but questions concerning the active conformation should be allowed. Now, 6MAM is stronger than diamorphine, but does that ester get broken down at all? Maybe that's why the formic ester was used. The levels of formic acid so formed would be so TINY as not to be important. The question is, what conformations can this substance conform to?
 
Oh, and don't forget 99% of opiates follow the morphine rule:-

1-Aromatic system
2-quaternary carbon
3-2 carbon chain
4-tertiary amine

This substance, like tilidine, most certainly do not. Anyone got the patent number for tilidine, BTW?
 
haribo1 said:
We are strictly avoiding sources & synthesis, but questions concerning the active conformation should be allowed. Now, 6MAM is stronger than diamorphine, but does that ester get broken down at all? Maybe that's why the formic ester was used. The levels of formic acid so formed would be so TINY as not to be important. The question is, what conformations can this substance conform to?
Click to expand...

if this is what you are asking regarding the 6MA ester breaking down, indeed 6-MAM hydrolyzes to M


what formic esterified structure are you alluding to?...6-MFM?
 
No the formic ester of the Lednicer compounds. There is a cyclohexanol (very similar to the cyclohexEnone in 6MAM but in the patent, formic esters are used.
 
well indeed formic esters are likely even more stable and lipophilic and as well in those amount there is no issue with using formic acid or consequential formaldehyde formation

which compound specifically were you looking at?

do you hae a copy of the table in the patent as in the patents that i access online it is omitted...?
 
Who is Daniel Lednicer?

The man made a OLR agonist active at the microgram level without resorting to a silly fentanyl with many, many isomers. But WHO is he? Is he alive or dead? Where dpes he work? How would one (hypothetically) get in contact with this dude?
 
I know he wrote The Organic Chemistry of Drug Synthesis, which you probably know too. The last one I have, which was published in 1990, lists him as working at the National Cancer Institute in Bethesda Maryland.
 
From the Library of Congress:

DANIEL LEDNICER has devoted his career in both the private and public sectors to the search for new therapeutic agents. A former chemist and project officer at the National Cancer Institute, he has held the positions of director of chemical research at Mead Johnson, director of pharmaceutical sciences at Adria Laboratories, and pharmaceutical manager at Analytical Biochemistry Laboratories. He is the editor of the Wiley series The Organic Chemistry of Drug Synthesis.

Library of Congress subject headings for this publication: Pharmaceutical chemistry, Drugs Synthesis, Drugs Design, Organic compounds Synthesis, Drug Design, Chemistry, Pharmaceutical methods, Drugs chemical synthesis, Chemistry, Organic methods
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