QSAR of Homologues of known Weak Opioid + extension of QSAR of a potent new Opioid.

[4DQSAR]

I was taking a quick look at 3-(dimethylamino)-2,2-dimethyl-1-phenylpropan-1-one. I discovered that the para fluoro and para chloro derivatives had been made and their analgesic activity tested.

So we have at least a little more QSAR data.

Original paper: 'Analgetics. II. Relationship between structure and activity of some beta-amino ketones'

Paper in which para halo derivatives are tested: 'β-Amino Ketones. Synthesis and Some Biological Activities in mice of 3,3-Dialkyl-1,2,3,4-tetrahydro-4-quinolinones and Related Mannich Bases'

H - 16mg/Kg
F - 45mg/kg
Cl - 85 mg/kg

Like all good research, a negative result is still a valid and useful result.

What REALLY astounds me is that while the original paper does include some ring-substituted examples, it only covers ortho hydroxy and para methoxy examples. The meta hydroxy is not explored.

A further search revealed a rigid analogue which WAS an opioid AGONIST (and important detail as affinity ≠ effacacy) in the papers:

Opioid agonist and antagonist effects of configurational stereoisomers of 3-(dimethylamino)-2,2-dimethyl-7-hydroxy-1-tetralol
Opioid receptor effects of two 3-amino-2,2-dimethyltetralin analogs in guinea pig ileum longitudinal muscle
Opioid receptor effects of two aminotetralin derivatives using the electrically driven mouse vas deferens

But I was unable to locate ANY of the above papers (anyone?). The tetralin being phenolic and chiral revealed what is quite common. One enantiomer being an agonist, the other an antagonist.

I think most people have missed the fact that the simple, weak opioid discovered in the 1960s is closely related to the much more potent (3R)-2,2-dimethyl-3-(dimethylamino)-3-phenyl-N-(2-phenylethyl)propanamide class which itself overlays BDPC and ciramadol. In that case the phenolic derivatives are far more potent BUT the raecemates at least are antagonists. The KEY breaktrhough made in the discovery of BDPC (and it's homologues) is the need for a para substitution of the A-ring. Why para methyl and para bromo are the only examples with potent agonist activity was a mystery even to the inventor. The phenolic homologues of BDPC are, likewise, antagonists. But Chinese researchers showed that substitution of the 2-phenylethyl moiety with a 2-(2-thienyl)ethyl (C-8813) increased activity by the same factor as replacing the same moiety in the fentanyl scaffold.

I will conclude by noting that the discoverer of BDPC was able to construct a Drieding model and show that in it's active conformation, it perfectly overlayed the active conformation of fentanyl.

https://pubs.acs.org/doi/pdf/10.1021/jm00196a001

Note that the two aromatic rings (RAs), basic nitrogen (PIF) and oxygen (ELA). To quote the paper '...the molecues can be arranged as to give point for point coincidence for all of the salient features.'

While it's exteremely difficult to predict the QSAR of a novel compound, I am able to go two steps beyond the original paper by stating that the (R) enantiomer is the active and that the dimethyl homologue is an order of magnitude more potent than the monomethyl amine. The fact that researcher did NOT produce this seemily obvious homoogue can be explained by the reluctance of researchers to explicitly state that they have discovered a new class of potent MOR agonist.

Bioorganic & Medicinal Chemistry Letters Volume 10, Issue 6, 20 March 2000, Pages 523-526
Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands

Note that my research was based on compound 4a. Resolution of the enantiomers proved that it was the (R) enantiomer responsible for ALL the MOR activity and that N-methylation (modified Eschweiler–Clarke reaction) increased analgesic activity by an order of magnitue. I draw your attention to norbromidol (N-desmethyl BDPC) which is known to be an order of magnitude less potent than the parent drug.

Financial limitations prevented the Ki, or EC50 from being established but from a purely practical perspective, a simple in vivo model provided far more useful information i.e. the ED50 was measured. The ONLY thing were were unable to test was non-phenolic ring-substitutions. But if anyone cares to model the named compound with BDPC they will appreciate that both aromatic rings, the basic amine and the oxygen lone-pairs perfectly overlay those of BDPC. It would be nice if someone with the appropriate software could confirm that an appropriate para substitution would alter the activity in the same maner as the BDPC class.

1 — Postimages

postimg.cc

The above image includes several benzylamine class opioids. The relative spatial position of the aromatic(s), basic amine and oxygen function remains constant among them. The doxicopamine analogue is interesting because it's ED50 is given as 2.4mg/kg compared to 1.7mg/kg for morphine. Doxicopamine itself is considerable less potent and behaves as a mixed agonist/antagonist much like ciramadol. The meta pyridyl moiety of doxicopamine acting as a bioisostere of a meta hydroxy.

 

[4DQSAR]

I forgot to mention that metofoline https://en.wikipedia.org/wiki/Metofoline#cite_note-10 is ALSO an example of a benzylamine opioids. Once again the (R) enantiomer is the (vastly more) active isomer. What is important is that the amine is within a semi-rigid ring system.

What it lacks is an oxygen function - a moiety that seems important to MOR affinity.

Evidently someone else noted this deficiency and lo, US Patent 3378561A details far more potent derivatives.

The paper 'Tetrahydroisoquinolines. I. The Preparation and Analgetic Activity of Some 1-Thiophenoxyethyltetrahydroisoquinolines and 1-Phenoxyethyltetrahydroisoquinolines' asserts tat compounds 13 and 14 are the most potent analgesics with an ED50 of 0.3mg/kg compared to 15mg/kg for codeine and 16mg/kg for dextropropoxythene.

So what insights can be gained? Well, that a para methoxy moiety is required for activity along with a meta methoxy - the novel class I mentioned showed that examples with a meta phenol moiety were robust ANTAGONISTS.

So I took the scaffold of metofoline and removed the meta methoxy moiety. Only the example was (1-(4-Nitrophenethyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. What I found interesting was that many suppliers offer this compound and it was assigned a CAS number.

The only reference given by PubMed is:

"medicinal chemistry: a series of monographs"., volume 5 (analgesics) page 291 1965

If anyone has accest the above, sharing would be much appreciated.

While it's clear that further work needs to be carried out, it does appear that ring-substitution is a topic worth considering. I am reminded that the meta phenol homologue of BDPC is an antagonist AND that the para bromine is required for the compound to be active.

Such research simply uncovers the fact that knowledge is much like a net, holes tided together with strands of data.

 

[4DQSAR]

DE Patent 1199775B & AT Patent 222120B includes tetrahydroisoquinoline compounds in which the meta methoxy moiety is excluded. No examples are given but the fact that the patent covers such compounds suggests that they are active.

It's worth noting that for the later tetrahydroisoquinoline developments in which the 2-phenylethyl moiety has a sulfinyl moiety inserted at the benzylic position, the para chloro homologue is more potent than the para nitro. That suggests that the beta aromatic better fits into a lipophilic pocket.

These insights suggest that for the novel class of potent opioid I referenced, it may be the case that replacing the meta phenol moiety which is required for antagonist activity may be substituted for either a single para substitution or a 3,4-disubstitution much like the tetrahydroisoquinoline class.

As a first step, a para methyl replacing the meta phenol would be the obvious first step. If the compound has LOWER affinity, clearly the approach is incorrect. If it doesn't alter activity compared to the non-phenolic Example 4a, it shows that their is at least sufficient space within the lipophilic pocket to allow further research. It's tempting to consider that given that the tetrahydroisoquinoline class is most active with a 3,4-dimethoxy substitution, disubstitution is likely to be the more active - but such research is incremental. If disubstitution fails, you have no idea if monosubstitution is a possibility.

BTW there are other examples. When a para nitro moiety is added to the B-ring of azaprocin, the chain-length is reduced to provide optimal activity.

I also recall 5-(dimethylamino)-4,4-dimethyl-1,5-diphenylpentan-1-one appearing in a book that classified opioids. So that benzylic dimethylamine moiety along with the dimethyl side-chains (to provide for a non-rotatable bond) is recognized as a key moiety. Replacing both aromatics with cyclohexyl rings was also demonstrated to produce an active compound.

The relavent article is 'Analgetic Activity of Some δ-Amino Ketones And Their Derivatives' in which naloxone was used to confirm analgesia was a result of opioid activity. Sadly the synthetic route employed precluded the aromatcs having differing ring-substitutions.

​

 

[4DQSAR]

BINGO!

I have noted that the most potent metofoline derivative was found to be the 'para nitro homologue. While I didn't overtly state the fact, I have noted that endorphins are pentapeptides and that if one counts the lonest chain-length, 15 is the magic number.

I haven't mentioned this before but I sent and E-mail to Dr. Danial Lednicer that simply asked 'is 15 the optimal chain-length?'

His response was somewhat reserved BUT he stated that 'while 15 appears to be the optimal chain-length, it's important to interrogate that active conformation of a MOR ligand. Linear compounds may damonstrate that a shorter chain-length is optimal while compunds in which folding takes place in the active conformation, longer chain-lengths may be longer.

So I will make it simple.

Take fentanyl, 4-phenylphenapromide, etorphine, etonitazene, BDPC or indeed ANY highly potent opioid and you will find that the most active homologue will almoes always have a chain-length of 15. There may be a side-chain that contains a second basic amine BUT that chaine-length it slmost always 15. Yes, there are examples such as the '2-fluoro derivatives of fentanyl are slightly more potent than the parent drug but in those cases, the affinity is actually lower BUT the EC50 is also lower i.e. the drug is more active because the modification increases the LogP and (a guess here), the binding (docking) conformation is lower than the parent and/or the LogP and or pKa of the derivative is more favourable(e.g. the 'para fluoro derivatives of fentanyl. have a Lower affinity, lower EC|50 but in vivo models show higher activity.

I can point to many examples in which within a series, the compound with the highest Ki was not the most potent. N-hnethylethyl noroxymorphone has a demonstrably higher affinity and higher Ki than N-phenylethyl morphine but the latter proved to be the more potent analgesic. The upside of that is codine is often avaiable without prescription and if one proceeds via the quaternary amine, it's a 2-step reaction to produce N-phenylethyl norcodeine. A compound several times more potent than morphine. If one is avle to perform the O-demethlyation, the morphine derivative is an order of magnitude more potent than morphine itself.

My on research revealed that the patent covering the 3-phenyl-3-amino-2-dimethyl propanamide class of MOR ligand revaled two important details:

1-Only one enantiomer posesses MOR affinity and this overlays ciramadol, doxicopamine and the other classes mentioned. The other appears inactive. Other possible ring-substitutions based on metofoline are purely theoretical. It seems more likely that para substitution of the B-ring would be more fruitful (and simpler).

2-To be clear, even the most active MOR agonist (3S)-2,2-dimethyl-3-(dimethylamino)-3-phenyl-N-(2-phenylethyl)propanamide only has similar affinity to compounds known to the art.

It's worth noting that the original research team suggested that the analgesic activity seen in the phenolic derivative (all of which had significantly higher affiity) was likely due to mixed agonist/antagonist (as seen in other classes). This would make them MORE appealing to manufacturers as such mixed action is considered have a lower abuse liability and lower physical dependence liability.

I will conclude that the MOST useful compound to test would be the example in which the 2-phenylethyl moiety (a common feature of potent opioids) is substituted for a 2-(2-thientyl)ethyl moiety. With BDPC, fentanyl and phenapromide derivatives, such a substitution increased activity by around 20%.