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The in silico design is definitely newer, the med chem students at my school are primarily computational chemists. They take organic classes but it's all stuff like docking and molecular dynamics, they have other labs synth their compounds for testing after high throughput virtual screening against protein structures obtained from crystals. It'll be interesting if we can one day get accurate folded structures without crystallization
 
You have to remember that when I studied medicinal chemistry, in-silico modelling didn't exist. People still built training-sets by hand, calculating the minimum-energy conformations but it was a VERY large undertaking. What ChemOffice will do in an hour would take many people many weeks of work. There are many tools for calculating docking conformity but like all in-silico models, they estimate and different tools will give different estimates. It's still likely to be the most efficient way to design new medicines but boy, do they throw up compounds that are complicated to make.

The fact that a drug that costs $100,000/Kg to make is only slightly better than one that only costs $1000/Kg to make is not considered, as far as I know. So while their is no argument that they ARE better, they aren't likely to be accessible by the majority of the peoples of the world.

Did you know that in the 1960s Janssen made a decision to stop researching the 3,3-diphenyl heptanone class of opioids in favour of the phenylpiperidine class because the latter is synthetically simpler. R-4066 was the kind of potency he sought but far, far too costly to make whereas fentanyl derivatives are quite cheap.

Since then a few other researchers have simplified the synthesis of 3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine] BUT it's still not cheap. I'm sure if Spiridone (or rather the acetyl ester of the methadol derivative) found a widespread commercial use, researchers WOULD find even cheaper routes as someone could get a royalty.

If you didn't know, their are specialist chemical companies who look at popular medicines and try to find cheaper syntheses. They don't MAKE the medicines, their income comes from selling or licencing their patented routes.

The entire drug development cycle is VERY complex indeed.
 

Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (<i>μ</i>, <i>δ</i>, <i>κ</i>), the <i>μ</i> (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are...
www.hindawi.com www.hindawi.com

I consider the above to be the index paper of the work by Helmut Schmidhammer who looked into the 14 substitution of phenanthracine opioids. It's interesting to note that he uses several chemically unrelated MOR/DOR ligands and examines the increased activity of such compounds.

14-methoxymetopon demonstrates the classic 'magic methyl' problem that is the bane of medicinal chemists. While alternatives to his synthesis exist, they are based on recent advances in organic chemistry and all are problematic. As it is he was forced to use methyl iodide and sodium hydride to methylate the quaternary hydroxyl moiety.

I did try to find facile alternatives but all of them proved to be lower yielding than his route.
 

An interesting modification of dextromoramide. It's a shame that the most facile synthesis still involves an SN2 reaction which results in a mixture of positional isomer. The PLUS side is that both the (R) and (S) enthiomers are virtually equal in activity so the raecemate is very likely a reasonable target.

Dextromoramide is generally accepted as being x3 morphine in potency and the above apparently has slightly higher affinity although interestingly, since it's an in-silico design, the researchers calculate in the energy lost due to binding rather than the more traditional Ki. I would be interested to know if the Ki can be calculated by energy value and vice versa.
 
vecktor said:
^ not a new compound at all. However the potency in vivo is nowhere near as high as is suggested by in vitro. ED50 32ug/kg in guinea pigs. In humans it is not that potent (fentanyl level potency)
Patent is 1972 to Sanko company, Chem Pharm Bull (Japan) 2050-2057 (1970)

I don't understannd this obsession with in vitro potency over everything, are you playing some kind of smackhead top trumps?

Safer opioids would be a good thing and super potent /= safer
Dezocine based compounds with reduced respiratory depression and or ceiling effect would be a better approach if harm reduction really was your priority
Click to expand...

I never claimed it was a new compound and actually included hotlinks to the references.

I am simply attempting to provide anyone interested with ALL the hotlinks I have access to so that they can study the various classes of opioid.

Sorry for the late response, I missed your post.

BTW elsewhere I have repeatedly stated that hugely potent opioids are extremely dangerous. Many people still rely on eyeballing doses so anything more than about ten times morphine in potency carries the extreme risk of overdose. When you reach compounds like carfentanil that are now on the street, it's reaching the limits of dilution when in a solid format. There are ways but it's not much of a surprise to realize that such compounds, compounds which find legitimate use in veterinary are produced as solutions.

It's also worth noting that potency varies between individuals and so while the press is keen to list carfentanil as x10000 morphine, the variability can be quite massive. It's a known issue within the field of anesthesia.
 

Above is a link to a fantastic paper which not only comprehensively documents the QSAR of every cocaine homologue documented, but it also correctly identifies the fact that methylphenidate and mazindol which chemically distinct, produce psychostimulation via the same pathways.

The other major class of psychostimulants are the amphetamines but people sometimes don't recognize that desoxypipradrol and homologues, nomifensine and homologues and various other stimulants such as fencamfamine (and homologues), phenmetrazine (and homologues) and even the 1,2-diaryl-2-amino-ethan-1-one derivatives all contain within them the alpha methyl phenylethylamine (amphetamine) scaffold within them*.

*In a few examples the benzene ring is replaced by other aromatic rings but such a modification appears to universally reduce activity.
 
Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Application to the synthesis of carfentanil and remifentanil

Tetrahedron Letters 2010-jun vol. 51 iss. 22, 2010

Author(s): Sandra Malaquin; Mouhamad Jida; Jean-Claude Gesquiere; Rebecca Deprez-Poulain; Benoit Deprez; Guillaume Laconde

Library Genesis

libgen.li libgen.li

Anyone wondering why carfentanil is now becoming common on the streets of North America need look no further. It's worth noting that the scope of the synthesis allows for the pendent benzene to be swapped for other aromatics AND the inclusion of a beta-hydroxy moiety which renders the products 6-8x more potent.
 
www.ncbi.nlm.nih.gov

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov

The mystery of 6,14-Endoethenotetrahydrooripavine.

The above link is a deep dive showing just how complicated the synthesis and isolation of etorphine actually IS. The truth is, it's unlikely to replace any of the black marked high-potency opioids soon.

But let's consider the first step. Thebaine (or in some cases oripavine) are reacted with a

dienophile noun di·eno·phile dīˈenəˌfīl
plural-s

definition:
the olefinic or acetylenic component (such as maleic anhydride) that is seeking a diene in the Diels-Alder reaction.

Now it's well known that 1,3-butandiene and ethene can be reacted to produce cyclohexene. There are MANY examples of this class of reaction being used to produce polymers. So one would think that the mystery compound would be a major product of oripavine and ethene. Not the ONLY product mind you because depending on the face being attacked, the -CH=C- bond could end up above or below the C-ring.

Now I actually DON'T think this is a major issue since hydrogenation yields the dihydro derivatives that appear to be uniformly more potent.

So potentially,, a compound listed as being some x400 morphine in potency is just two steps from oripavine (which isn't mentioned in the UNODC list of controlled drugs and seeminly isn't a controlled precursor.

So IF I had to guess, I would guess that...

(6R)-11hydroxy-15-methoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-triene

AKA

6,14-hexahydrooripavine

WILL be a reasonable candidate.

614H
 

Library Genesis

libgen.li libgen.li

Above is the original paper discussing the extreme potency of BDPC. What is so fascinating is that Lednicer et al. were able to construct a Dreiding model which shows that the compound can perfectly overlay fentanyl.

'The two benzene rings can be directly superimposed (though the link to the rest of the molecule is rotated by 60'). The basic nitrogen atoms of the two molecules similarly fall in the exact same spot in space as do the extreme right-hand benzene rings. The hydroxyl
group in 1 falls in the middle of the amide function of fentanyl.'

I think this especially useful for students who struggle to visualize a chemical in 3D. When drawn in 2D two compounds may look entirely unrelated but in fact, overlay perfectly in 3D.

Other examples of this are U-47700 perfectly overlaying prodine or 4-phenyl phenapromide perfectly overlying fentanyl. I can extend this to other classes but I've stuck to the class of compound of with I am (fairly) certain of the 'salient features;.
 
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