Morphine - how the pharmacophore was used to design opioids

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I post the above showing the 5 rings present in what are termed phenanthracene opioids.

Morphine is still the 'gold standard' and is the prototype opiate.

I'm hoping people understand how those lines that get thicker at one end represent atoms in front of and behind the plane of the image although be aware, it's still more of a diagram than an image i.e. it accurately demonstrates how the atoms are connected, but not the true 3D shape of morphine.

 

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Here is a selection of phenolic (all with an -OH on that benzene ring) opioids. Often they are drawn in differing orientations in textbooks so I've redrawn them so you can see how each on has retained the A-ring (at least) which is a clue to it being a required element of the pharmacocore.

I haven't strictly drawn from weakest to strongest, oldest to newest BUT it's worth noting that the last three are all in the region of hundreds to thousands of times more potent than morphine... so you might note that they all have an EXTRA aromatic.

Knowing that will be important for later when I explain why fentanyl, BDPC, etonitazene and such are all so potent.

 

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But let's take a step back. The other natural opiate found in opium poppies is codeine. In the 1920s German chemists had recognised that codeine was less dependence forming and so sought to combine this advantage with improved analgesic activity. In all cases, the only modifications are to the C ring.

If one removes the 3-methyl ether (the CH3- protecting the phenol) then we get the above. The codeine series.

 

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The Germans wondered 'just how potent can we make the morphine structure JUST by modifying the C-ring?'

 

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Pretty good, as it turned out. The potency of the above are x2, x10, x50 and x50 morphine.

ALL just by modifying the C-ring. Of course most modifications didn't improve potency but all the time rules were being discovered.

 

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Note how N-substitution can produce antagonists, and mixed agonists... but swerveball, some compounds with N-methyl substituents can also be mixed agonists.

 

[izo]

there are some places to boost potency, many changes at the 6 position yield more active derivates, then n alkylation and the modification at the 14 position. if you combine them all and modify dihydroetorohine that way you maybe get something even more potent.

 

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there are some places to boost potency, many changes at the 6 position yield more active derivates, then n alkylation and the modification at the 14 position. if you combine them all and modify dihydroetorohine that way you maybe get something even more potent.

With the etorphine series, the extra ring means all four bonds at the 14C are used.

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How about this little find - tilidine is a BU48 fragment. It explains why things like BDPC are so active - their are two distinct points within the receptor domain that bind via ionization.

I placed the ester functions out of the way but note that the ester-amine is in a trans relationship so in fact, if drawn accurately, the esters would overlay the O of the D ring behind the amine (from the view provided).

 

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Ciramadol was the first example I gave, to make people think. It appears that while MOR ligands require a positively ionizable function, their appears to be two sites within the receptor domain as BU72 demonstrates (and explains why nortilidine, ciramadol and such are active.

Taking it a little further, BDPC has been tested and indeed tasted so we can confirm that it is a MOR agonist. But it only has trans-cis isomerism.

I found a new class of opioid (posted elsewhere) and it would appear that the PIF and and a specific HBA (so -OH or =O) can be swapped.

Counter-intuitive BUT luckily we have a (partial) example of this phenomenon.

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The obvious step would be to ask the discovered of BDPC if that is indeed the case. Sadly Dan passed on a couple of years ago BUT like BPDC, the phenolic examples of the 3-amino-3-phenyl propanamides are ANTAGONISTS but the non-phenolic examples are AGONISTS... so would a p-Br improve the affinity of the unexplored class?

 

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What O have been slowly leading up to is the question of the unknown. Will an N 4-phenylpiperidine work similarly to phenapromide OR will an N-methyl-N-phenylethyl be active?

PubChem has some closely related compounds that appear to be NOP ligands. Of course, since their don't appear to be any human studies on dimethylaminopivalophenone, it's possible that the parent compound itself is a (weak) NOP ligand.

In ChemOffice it was interesting to note that dimethylaminopivalophenone overlays 3,3-dimethylprodine and that dimethyl moiety is included (as far as I can tell) to reduce the count of rotatable carbon bonds and it is seen in other classes of drug for that reason.

 

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I'm sure those who are familiar with the problems of drawing a 3D structure onto a 2D plane will appreciate that the images are part conformational information and part diagram - an unavoidable problem.

But the key thing to note is that the -OH in Z4249 closely overlay the 14 -OH of oxymorphone.

Now early papers suggest that the chiral N substitution produce both agonist (R,R) and antagonist (S,S) enantiomers. But later papers concluded that this was in fact NOT the case.

A phenol or bioisostere thereof is required to engender opioid activity.

The -Cl is a HBA which is why the -F homologues are MORE potent (as F>Cl>Br>I). It's worth noting that the phenol of the phenanthracene/morphinan/benzomorphan scaffolds has successfully replaced with a carboxamide (-C(O)NH2) moiety. Aromatic nitro groups can also be used in limited circumstances but increase the isosteric bulk.

 

[kokaino]

The opiates of greatest interest to me are morphine, and the 3,6-diesters of morphine. Even though many are morphine prodrugs.

 

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The opiates of greatest interest to me are morphine, and the 3,6-diesters of morphine. Even though many are morphine prodrugs.

Well, their is a lot of research out there but essentially 3,6-diacetylmorphine is the most active. I think the NHS trialled dibenbzoylmorphine some years ago and it had no clinical advantage.

 

[kokaino]

Well, their is a lot of research out there but essentially 3,6-diacetylmorphine is the most active. I think the NHS trialled dibenbzoylmorphine some years ago and it had no clinical advantage.

I thought nicomorphine is still used in Germany and Austria?

The others that interest me are desocodeine and desomorphine.

 

[kokaino]

Apparently, the Health Committee of the League of Nations described 3,6 dibenzoylmorphine as being virtually identical to heroin and morphine in its effects in 1930.

 

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Indeed - the NHS only uses diamorphine when analgesia is time-critical BUT it was found doctors who might usually have administered 10mg of morphine would mistakenly just think 10mg of diamorphine was equipotent (diamorphine is only rarely used) so the point of dibenzoylmorphine is that those two heavy benzoyl esters increase the MW of the drug it IS equipotent.

As for desomorphine, it was only used in Switzerland and only briefly during the 1950s. It has no clinical advantage over diamorphine.

I mean, it's onset is as fast as H but it's duration of action is shorter and their aren't many situations in which fast onset and short(ish) duration are ideal. So, again, it wasn't used much because it had no clinical advantage.

I've actually posted a thread on why Korkodil is so toxic. Put simply, if one uses RP/I to convert codeine to desomorphine, the phosphorous can react with the codeine and form phosphonate esters which are VERY toxic. Pure desomorphine is risky enough but some random mixture of compounds... insane.

 

[kokaino]

Indeed - the NHS only uses diamorphine when analgesia is time-critical BUT it was found doctors who might usually have administered 10mg of morphine would mistakenly just think 10mg of diamorphine was equipotent (diamorphine is only rarely used) so the point of dibenzoylmorphine is that those two heavy benzoyl esters increase the MW of the drug it IS equipotent.

As for desomorphine, it was only used in Switzerland and only briefly during the 1950s. It has no clinical advantage over diamorphine.

I mean, it's onset is as fast as H but it's duration of action is shorter and their aren't many situations in which fast onset and short(ish) duration are ideal. So, again, it wasn't used much because it had no clinical advantage.

I've actually posted a thread on why Korkodil is so toxic. Put simply, if one uses RP/I to convert codeine to desomorphine, the phosphorous can react with the codeine and form phosphonate esters which are VERY toxic. Pure desomorphine is risky enough but some random mixture of compounds... insane.

Diamorphine's potency over morphine is often exaggerated. At most, it's 2x more potent. An old German medical manual estimated that 6.5 mg of H is equivalent to 10 mg of M. Produces more pronounced respiratory depression than both.

Desomorphine was described as 15x more potent than morphine and 5x more potent than oxymorphone. Yes, that Krokadil stuff was definitely not pure deso.

 

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The three references I have (including the original Swiss PIL) suggest that desomorphine, for medical purposes, should be considered 10x morphine in potency.

This assumes intravenous administration of course. Oral conversion gives quite different values but I use IV because it essentially assures (almost) 100% bioavailability.

It's also worth ensuring that you adjust for the mass of the addition salt. Diamorphine generally comes as it's hydrochloride salt, desomorphine as it's hydrobromide salt and morphine as it's sulfate salt although morphine phosphate and morphine hydrochloride are also used medically. So differences may well be due to some people applying the potency conversion to the addition salt of the medicine while others calculate based on the MW of the freebase. From the perspective of a doctor who doesn't care about the nature of the addition salt, using the MW of the salt is more appropriate but for a medicinal chemist, it's more appropriate to use the MW of the freebase. Modern literature will often provide a 'conversion factor' i.e. a faction to multiply the weight of the salt by to get the MW of the freebase.

The choice of addition salt is generally down to stability, solubility, bioavailability and convenience (generally in that order). I don't mean absolute bioavailability but rather the pKa. Only the freebase can pass the BBB so how quickly the salt is removed can alter the onset and peak.

Krokodil is, I presume, the hydroiodide salt which is yet another reason why it's such a bad idea.

But then Russia is the only nation to see tropicamide abuse and I have NO understanding of how someone decided that injecting eye drops was a plan. I believe it was also Russians who first discovered that tianeptine was an opiate but others have noted that in solution it quickly turns into a polymer and described it as being 'like superglue' and so people IVing that were losing limbs or their lives.

At the end of the day each of us is different. So any figure given is only a rough guide and doctors know this and know they may have to titrate the dose if they swap between two similar but distinct medicines. Opioids behave differently between ethnic groups so it's difficult to designate numbers unless you have data from very large international sets of studies.

For my money, the most interesting component of Krokodil is methyldesorphine. It's only turned up in trace amounts but it MAY have a significant impact on and values given for the stuff.