Simplification of phenanthracene scaffold

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Library Genesis

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The above link confirms that (R)-3,3-dimethylprodine is 7.5-10x morphine in potency.

Library Genesis

libgen.pm

The above link confirms that compound 29 has the same potency of pethidine.

What the above demonstrates is that three compounds that when viewed as CONVENIENT 2D images fails to demonstrate the common core and what constitutes the pharmacophore of mu ligands. These compounds all follow what is commonly known as 'the morphine rune', an early attempt to define structural features that provides affinity:

1-Aromatic System
2-Quaternary Carbon
3-two carbon chain
4-Tertiary amine

While MANY opioids deviate from these rules, it holds true for around 90% of known opioids.

If people wonder why I chose 3,3-dimethyl prodine, it's to demonstrate that a second quaternary carbon increases affinity by the simple expedient of reducing the number of rotatable carbon bonds.

People may well be aware that the potency of both oxymorphone and 3,3-dimethyl prodine may be greatly increased by replacing the N-methyl with an N-(2-phenylethyl) moiety. This is also likely possible for the simplest example by replacing the dimethyl for a 4-phenylpiperidne moiety which overlays the N-pe moiety and indeed closely related compounds are known.

But as an exercise, count how many atoms make up each molecule and thus the MW. You will note that potency is given in mg/kg so the lower the MW of a compound, the more molecules per given mass and so atom for atom the three compounds are closer to being equal in activity.

 

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BTW if people wonder why the loss of that ester function affects potency so much -clearly it's because their is an amino-acid residue in which a -COOH moiety seeks to form hydrogen bonds. An intermediate compound is phenapromide (x0.7 morphine) and it's 4-phenyl derivative which is x60 morphine i.e. 85x more potent.

The KEY it that carboxylic acids behave as zwittrions i.e. the H of the C(O)OH rapidly switches between the two oxygens and thus a moiety with 2 hydrogen-bond acceptors one methylene (-CH2-) apart will bond with the highest affinity.

It's important to remember WHAT affinity IS.

It's the introduction of a compound that allows the existing amino-acid complex assume a lower energy-state.

People may ask why a compound does not remain bound. Well, a number of reasons. The zwittrionic nature of amino-acids being one, the fact that the body thermally introduces energy into the system and the fact that the body produces natural ligands.

Now irreversible ligands DO exist. These generally form a co-valent bond to the receptor and their duration is generally long. But even when bound such compounds are not protected from all metabolism and they tend to result in apoptosis and internalization of the receptor.

Opiates such as oxymorphazone are the best known of these. Their activity tends to mirror that of their parent compound BUT what they ALL produce is 100% receptor occupancy which results beta-arrestin internalization i.e. tolerance increases RAPILDLY.

The first irreversible ligands were discovered in the 1950s and MIGHT have given Burroughs's 'dream' of 'chlorophyll addiction' in that '1 hit and you are hooked'. There are fentanyl derived irreversible ligands and the long, long duration of action mentioned by a few users could be the result of someone semi-legally obtaining such compounds.