Novel Opioids

[3DQSAR]

Here's the synthesis: https://ibb.co/w7fm10w

The Strecker-like condensation between N-benzyl-4-piperidone [3612-20-2] (1), KCN and PhNH3+Cl- gives 4-anilino-1-benzylpiperidine-4-carbonitrile [968-86-5] (2). Acid catalyzed partial hydrolysis of the nitrile to the amide afforded 4-anilino-1-benzylpiperidine-4-carboxamide [1096-03-3] (3). Reaction with formamide serves to form the spiroimidazolidone ring giving 8-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one [974-41-4] (4). Catalytic hydrogenation then removes the benzyl group (5).

[1] Goebel, Tim; Ulmer, Daniela; Projahn, Holger; Kloeckner, Jessica; Heller, Eberhard; Glaser, Melanie; Ponte-Sucre, Alicia; Specht, Sabine; Sarite, Salem Ramadan; Hoerauf, Achim; Kaiser, Annette; Hauber, Ilona; Hauber, Joachim; Holzgrabe, Ulrike (2008). "In Search of Novel Agents for Therapy of Tropical Diseases and Human Immunodeficiency Virus". Journal of Medicinal Chemistry. 51 (2): 238–250. doi:10.1021/jm070763y.
[2] Janssen Paul Adriaan Jan, US3155669, US3155670, US3161644 & US3238216 (1964, 1964, 1964 & 1966 all to Research Laboratorium C Janssen NV).
[3] W Scharpf, US3839342 (1974 to FMC Corp).

Why not test the benzyl group is already strong enough without needing to deprotect and replace with another sidechain?

Without yields and details on the workup, it's not clear how much work is involved. But I did read the Janssen patent and it doesn't look like a simple matter. As I mentioned, the intermediate is used in the synthesis of a neuroleptic so in theory at least, it's an item of commerce.

While I appreciate a lot of vendors offer the material, it's quite likely that they are just buying the intermediates. It's not as costly as one might think, but obtaining it at scale might well be an issue. By CHEAP I mean $120-$200 per GRAM. So suddenly that SN2 N-alkylation needs to be optimized. Cs2CO3 appears to be the base that produces the highest yields in related reactions but I'm uncertain of it's solubility and indeed the scalability of such a route.

So while I'm sure it's quite simple to produce a few grams, I suggest one might need to look VERY closely at the syntheses of fluspirelene. US 3238216 covers it and a lot of other patents cite it so there is almost certainly at least SOME optimizations disclosed.

 

[LucidSDreamr]

Some of these compounds are very easy to make are the my super potent or takes tens of milligrams for an effect?

 

[Smyth2]

Spirochlorphine has been advertised as 2-5 times the potency of fentanyl.

Remember when you measure these things it's best to make a stock solution.

20 drops of water = 1ml.

 

[3DQSAR]

Spirochlorphine has been advertised as 2-5 times the potency of fentanyl.

Remember when you measure these things it's best to make a stock solution.

20 drops of water = 1ml.

As analgesics - as I mentioned earlier, it may be the case that they are more potent NOP agonists than MOP agonists.

Certainly the later work builds on establishing a QSAR of MOP affinity, which after quite a lot of research, hasn't resulted in a medicine thus far. Some opioids do have significant NOP affinity with buprenorphine being one example.

I just realized that I had read the Janssen patents before Mollereau et al. had formally identified the NOP receptor. I did search for any papers associated with the patents but found nothing of use. I DO remember that the patent assigned analgesic activity to the parent compound s x500 M but the 'p-Me (para methyl on pendent benzene) as x500 M. I note that brorphine has a p-Br in the same spot.

But I'm sure people are aware of how crude analgesia is tested on animals. No sign that they had ever used rats that had been trained to discriminate by using another opioid. But I haven't read the Chinese papers, so there we are.

As far as I can tell, the (S) enantiomers are the more active.

I suggest that the (pare substituted) benzylamine moiety is more likely to had significant NOP affinity in both classes BUT there are patents that use that spiro moiety with the classical 3,3-diphenyl moiety. Be it with a 3 nitrile (producing a bioisostere of bezitramide) or with a 3 propan-1-one (producing a bioisostere of methadone) - R5260. I believe the activity of those WAS studied... by the US Army, of all people.

It it worth reading about NORbezitramide. Not the prodrug, the active. It's a lot more potent than most people imagine. It also displays a non-linear curve of dose/response when compared to morphine. There were several studies and while 5mg of norbezitramide roughly equated to 50mg of morphine, 10mg equated to 130 mg of morphine and 16mg (the highest dose tested) appeared to equate to roughly 230mg of morphine. I feel I should make it clear that while quite well designed, the cohorts involved suggest it only reached stage 2 trials. Nobody conclusively stated why it wasn't further developed.

But when you read 'McDermott's Guide to the Depressant Drugs', you realize that norbezitramide is far from unique. To paraphrase the author on the topic of Palfium (dextromoramide) 'one day you can take 5 pills and be fine, the next day take just 3 and end up slumped in the corner turning blue'. I don't quote this for shock value, but to highlight the fact that some opioids are inherently unpredictable.

I have to respect the fact that Janssen were able to find an island of activity (dextromoramide being around x3 morphine) in a sea of closely related compounds with much less (<10% morphine) MOR activity.

Sorry to belabour the point, but I felt it important to ensure that anyone studying the class should be aware that these issues exist.

FYI until a couple of years ago, dextromoramide was still prescribed in The Netherlands to treat opiate dependency. The reason was that dextromoramide produces an IV-like rush even when consumed orally. I'm uncertain as to why it's use has been stopped but if patients were entrusted with tablets, IV dextromoramide abuse was infamous in the UK, such was the mortality rate.

 

[krkkhed]

I didnt know it was a k agonist. I havent tried any k agonist's yet unless you include salvia that is lol. I would like to try something like talwin or Stadol even but i have never heard of either being scripted here. Or any k agonist really

I have an anecdote that maybe doesn't fit here completely but it is relevant to Salvia. I've done Salvia many times, from 20x extract to even 120x. I've smoked it beside multiple friends out of the same bong and pipe on other attempts, right after them, holding it and all that special stuff, and I never get more than an extremely intense physical feeling that seems like most peoples experience with Salvia physically, but like almost no visuals, only slight distortions on 80 and 120x extract.
Not sure if I'm immune because those friends beside me had full on trips, I never did. Always has perplexed me...obviously the extracts might be bunk or whatever but that's why I mention my friends, because they always had full on experiences but I never did

 

[3DQSAR]

I was informed by @fastandbulbous that kappa agonists all appear to produce those severe psychiatric side-effects. Now I didn't ask them WHICH kappa agonists or how many, but I am aware that they are slow to ever state a fact and are traditional in their evidence gathering. I know both of us are old enough to have been around when suppliers of 'receptor probes' weren't nearly as careful who they sold to, so such unusual items were available to those who could fake a business address.

They don't sound too good.

For me, the salvia experience isn't one I would wish to repeat. Heavens knows what a longer acting agent would be like.

 

[Smyth2]

On the EADD forum someone was talking about trippy heroin being more dysphoric than his regular stuff.

Someone said that is nitazines that do that but I immediately thought to myself it could have been due to kappa agonism.

When I went to Bath university for an interview with Dr Stephen Husbands we discussed that kappa antagonism was a novel target for antidepressants.

However, a number of the mixed opioids he had made over the years had kappa agonism as a part of their pharmacology.

I said to him that I would expect this to be dysphoric but he sort of laughed and said that to some addicts it might be agreeable.

I have a large number of KOR agents in my personal database. If anybody is interested I could make a list of them to discuss but it probably belongs in its own thread.

 

[3DQSAR]

I can confirm that Afghani (brown smoking) heroin is subjectively different from medical diamorphine hydrochloride (which is still used in the UK). IIF I hat to guess, I would suggest that papaverine is the likely reason. MANY years ago I ran into someone who was prescribed dry-amps of diamorphine as part of HAT. He would sell them to buy brown. Junkies in the UK and possibly those in nations where both brown and white heroin (the latter coming primarily from the Shan States) will often have a preference. Generally for brown.

Most users typically consider pure diamorphine to be too subtle, too clean and less euphoric. There is a lovely passage in the book 'Songs They Never Play on the Radio' in which John Cooper Clark and a member of The Faction (Nico's backing group in her early 80s tours) discuss the topic.

Now the nitazenes are an interesting class of compound. If one reads all of the papers and patents, it's clear that the researchers had discovered that the 2-benzyl benzimidazole scaffold displayed a variety of activities. When you read the papers in order, it becomes apparent that it was a de facto tour de force in QSAR analysis. I recommend it to anyone so they can understand how rational design is undertaken. I know, it's the old way of doing things BUT it does mean one can usually find a compound with the sought activity with the minimal amount of synthesis. I can only assume RC designers still use that methodology. I DOUBT HTS has taken off.

Now the prototype opioid, etonitazene is often classified as a selective MOR agonist but there are constantly new analogues turning up and we don't know much about them. I think this is a good article on the topic:

Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene - Archives of Toxicology

Following isotonitazene scheduling in 2019, the availability of alternative 2-benzylbenzimidazole opioids (nitazenes) on the global drug market increased, resulting in many fatalities worldwide. Nitazenes are potent µ-opioid receptor agonists with strong narcotic/analgesic effects, and their...

link.springer.com

I'm sure people are aware that one of the KEY reasons that clandestine chemists alighted on the nitazenes is:

Etonitazene. An Improved Synthesis.
F I Carroll, M C Coleman
Journal of Medicinal Chemistry , 1975. Vol. 18. No 3
DOI: 10.1021/jm00237a024

Reports here on Bluelight seem to suggest that the nitazenes in question monkey around with extracellular monoamine levels. I've read reports of people kept awake all night next to reports of people gouching out for many hours. I have no idea if they were using the same chemical.

Unlike the fentanyl derivatives, it does appear that the nitazenes are more accepted and indeed sometimes preferred by users. Manufacturers aren't dumb. They do (or at least did when it was legal) send out samples and ask for reports. So I assume they have worked out the best analogues.

But what I have noted time and time again is that high potency opioids all seem to display two problems. One is their activity differing hugely between users, the other is that mostly they aren't particularly euphoric. IF some of the nitazenes solve the latter issue, then we are going to see a huge problem.

I've had the chance to sample many opioids and nortilidine stands out because it's an opioid AND a psychostimulant. Those with ChemOffice might benefit from overlaying nortilidine and cypenamine. AFAIK the reversed ester (sort of) nortilidine precisely overlays cypenamine. I still would not recommend opioids to anyone but I can appreciate the fact that being only around the same potency of morphine, it's rather less likely for someone to accidentally OD.

I find it a fascinating class because we are still discovering novel ligands but I think JCC sums them up perfectly. 'First it's fun, then it's not, then it's hell.

 

[3DQSAR]

BTW metofoline is very similar to papaverine. I can remember finding a second round of research on the class while reading an old copy of 'Annual Report in Medicinal Chemistry'. Bristol-Myers discovered that a slight structural modification resulted in significantly more activity. Bear in mind that the class has a benzylic amine moiety so I suspect that a training-set involving the class along with BDPC (and derivatives), ciramadol, doxicopamine, 3-OH PCP (and derivatives) along with certain of the 3-amino-3-phenylpropanamides,... and almost certainly a few others that escape me for a moment.

ONE thing that's apparent is that in those with chiral amines (N,N-dimethyl appearing optimal), MOR activity resides in the (R) enantiomer.

If anyone can add to more examples of MOR ligands with a benzylic N,N-dimethylamine moiety, we can refine the training set!

 

[3DQSAR]

The aminotetraline class of opioids are mentioned as weak opioids in quite a few textbooks but it appears that researchers spent decades finding more potent examples. There are some quite complex derivatives in later papers but I though I would pop this one here as it's a rare example of a MOR ligand with a primary amine.

To be clear, affinity ≠ activity. Years of research has led me to suggest an extra QSAR for MOR ligands, to whit:

An antagonist ligand requires the presence of a phenol or bioisostere thereof.

Sci-Hub | Synthesis and Structure—Activity Relationship of Novel Aminotetralin Derivatives with High μ Selective Opioid Affinity. ChemInform, 34(8) | 10.1002/chin.200308090

Interestingly, the primary amine (compound XV) appears to be an agonist according to a later study:

Sci-Hub | Identification of a New Scaffold for Opioid Receptor Antagonism Based on the 2-Amino-1,1-dimethyl-7-hydroxytetralin Pharmacophore. Journal of Medicinal Chemistry, 47(21), 5069–5075 | 10.1021/jm040807s

BTW I found the above by interrogating PubChem for compounds related to dimethylaminopivalophenone. I do appreciate that this compound is very similar to pethidine (Demerol) and so not hugely potent, but I would argue that it is, by far, the simplest fully synthetic opioid in terms of it's structure and it's preparation. One step.

<EDIT>US Patent 6844368B1 'Compounds useful in pain management'</EDIT>

 

[3DQSAR]

Sci-Hub | Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods. Journal of Molecular Modeling, 17(3), 477–493 | 10.1007/s00894-010-0745-1

Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods
Jianxin Cheng & Guixia Liu & Jing Zhang & Zhejun Xu & Yun Tang
J Mol Model (2011) 17:477–493
DOI 10.1007/s00894-010-0745-1

While I'm not certain, I suspect that Cm4 might represent the 1,3,8-triazospiro[4.5]decan-4-one derivative with the highest MOR affinity 0.21nM. But as I am always keen to point out, affinity ≠ activity and often the EC50 is the better indicator of activity. I think I am correct in saying that examples in which the NH moiety is substituted were explored and appeared to have increased NOP affinity.

It appears that researchers used:

Jordan AD, Orsini MJ, Middleton SA et al. (2005) 8-(Heteroaryl) phenalkyl-1-phenyl-1, 3, 8-triazaspiro[4.5]decan-4-ones as opioid receptor modulators. Med Chem 1:601–610

Once again, note that the paper used the term 'modulator' rather than 'agonist'. But with no phenol or obvious bioisostere thereof, it's likely to be an agonist.

 

[3DQSAR]

Sci-Hub | Synthesis and structure–activity relationship of novel aminotetralin derivatives with high μ selective opioid affinity. Bioorganic & Medicinal Chemistry Letters, 12(21), 3141–3143 | 10.1016/s0960-894x(02)00644-3

Interesting that seemingly such simple compounds appear to display quite potent analgesic activity.

The fact that the homologue with a -SCH3 moiety is more potent than that with an -OCH3. Now this could be a valuable insight. Such a small fragment displaying activity several times that of morphine is somewhat unexpected.

 

[3DQSAR]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Title
8-(Heteroaryl)phenalkyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as opioid receptor modulators

Abstract
A series of N-biarylalkyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones were prepared and evaluated for biological activity at opioid (mu, delta, kappa) and opioid receptor like-1 (ORL-1) G-protein coupled receptors. Substitution on the biaryl moiety produced enhanced affinity for the mu-opioid receptor.

Now since the discovery of the N-benzyl homologues, there was a second wave of interest centred around the class as NOP (formally known as ORL1) ligands but, as we can see,:

R-5260

R 5260

R 5260 | C31H35N3O2 | CID 3081947 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

And a little earlier (based on the numbering), the 2-benzimidazoline analogue.

R 4837

1,3-Dihydro-1-(1-(4-oxo-3,3-diphenylhexyl)-4-piperidinyl)-2H-benzimidazol-2-one

1,3-Dihydro-1-(1-(4-oxo-3,3-diphenylhexyl)-4-piperidinyl)-2H-benzimidazol-2-one | C30H33N3O2 | CID 98813 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

When one also considers:

R 4066

R-4066

R-4066 | C32H37NO | CID 380029 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

That last one apparently sometimes referred to as 'Spiridone'.

I suggest that what all three provide in terms of MOR affinity is a lipophilic RA in an appropriate relative spatial position to the key moieties described in the paper that employed a training set. that those bearing a ketone are the more potent may provide a bioisostere of a ketone or hydroxyl moiety on the carbon adjacent to said aromatic. Let us not forget that such substitution had been shown to increase MOR activity in a wide range of opioids.

Now it's also important to note that the researchers further refined R 4066.

Sci-Hub | Synthesis and analgesic activity of some long-acting piperidinospiro derivatives of methadone. Journal of Medicinal Chemistry, 21(5), 474–476 | 10.1021/jm00203a014

Given that ORLAAM made use of the differing activity of the two isomers of the acetyl ester derivative, R 4066, it seems likely that the other compounds might also see increased activity. If I were a betting man, I would suggest that the (S) enantiomer is the more active.

Levomethadyl Acetate

Levomethadyl Acetate | C23H31NO2 | CID 15130 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

But I think it's worth reflecting upon the fact that ORLAAM was withdrawn due to it's cardiotoxicity. When one is considering novel agents, it's important never to lose sight of the fact that some examples will display activity at other than that sought.

BTW I would consider these to be unusual examples of the 3,3-diphenyl heptanone class (as Janssen named them). Lest we forget, methadone is considered the first synthetic opioid arrived at entirely via rational design. So even in the late 1930s, their evidently were people using notebook and reference in pursuit of identifying the key moieties.

 

[Smyth2]

I was the first person to start calling R 4066 spirodone because of it's spirocyclic structure.

As the time though, I was unaware of the spiperone piperidine compound R-5260, which is likewise spirocyclic.

I think these compounds above are good but R 5260 only has patented literature and no mention of it being 200 x the strength of methadone.

The nitrile nor methadone compound appears in a more recent patent than the original 1960s Janssen patents:

Zhengming Chen & Sam F. Victory, WO2003101953 (Purdue Pharma LP).

 

[3DQSAR]

Well you will notice that PubChem also uses the name Spiridone BUT I've rediscovered and named a couple of things that PubChem also uses as one of there names so clearly it's possible. So well done on that

I found several values for the potency of each of the compounds I mentioned but as I have noted elsewhere, animal models are often WAY off the mark so are possibly less useful that they might appear. Especially if compared to a drug somewhat famous for having been assigned a range of potencies.

I just wanted you to be aware that these compounds were all apparently tested in the 1960s or 1970s and appear to have more selective MOP affinity. I have to ask why NOP ligands haven't found their way into clinical practice. It's true that several opioids introduced before the NOP receptor was elucidated but as far as I know, none exert the bulk of their analgesic activity via NOP. One reads how much better NOP ligands may be in the treatment of chronic pain - and as someone who has been prescribed a lot of opioids for years, I can confirm that you do have to slowly increase the dose or swap to a stronger opioid due to tolerance. Nothing crazy. A given dose will work for several years.

I've found that if one takes a simple compound and pastes it's SMILES definition, it's often useful in discovering what if any derivatives have been studied. It was Dmethylaminopivalophenone that threw up the 3-dimethylamino)-2,2-dimethyl-7-hydroxy-1-tetralone derivatives.

While the paper 'Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods' is of some use, I think it's clear that there are more key moieties. So, with Open3DQSAR, it's in theory possible to provide a much larger training-set with the goal of identifying more structural features.

To be clear, I'm not suggesting that Open3DQSAR is necessarily the best tool but it's free so quite literally anyone is able to take part. I'm unaware of a decent alternative to Chem3D but it's worth noting that older versions turn up on eBay and similar. It's arguable that versions 18 and later are less friendly and are rather intrusive.

 

[3DQSAR]

d hosted at ImgBB

Image d hosted in ImgBB

ibb.co

S Wilkinson and P Cuatrecases, Biochem Bwphys Res Commun 74, 1311 (1977), M C
Fournie-Zaluski, R Pednsot, G Gacel, J P Swerts, B P Roques, and J C Schwartz,
Biochem Biophys Res Commun 91, 130 (1979)

The above is a rigid analogue of dextropropoxythene. Useful in a trial-set. It's potency is stated as being x5 morphine. There are a few other tetrahydronapthalene derived opioids such as desocine although most of them are less potent.

I don't know if it's just me but I cannot find these references or indeed the structure.

 

[3DQSAR]

Sci-Hub | | 10.1038/s41598-020-62530-w

There are dozens of papers by Helmut Schmidhammer but I find this one to be of most practical value.

 

[Smyth2]

Sci-Hub | Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties. Journal of Medicinal Chemistry, 26(1), 42–50 | 10.1021/jm00355a010

It's taken me a little while to find an index paper for the obscure (but potent) class of opioid analgesics developed by Sandoz. Compound 47 is the most potent in animal models.

It should be noted that the authors actually state that analgesic activity is between x30-x200 morphine depending on the test employed. To me, that seems a HUGE range.

As to why the racemate is more potent than either enantiomer is just one more unanswered question. But note that at this stage, nobody had recognized that for a compound to demonstrate antagonist (or inverse agonist) activity, it HAS to have a phenol moiety or bioisostere thereof.

The fact it only ever reached preclinical trials MAY suggest unpredictability. Note the reference to the earlier U.S. Patent 4178377 upon which this paper is largely based.

Still,, this compound apparently has affinity to all four classes of opiate receptor ALTHOUGH I must add the caveat that the affinity studies were carried out in the Norwegian rat. Still, it's another class that can be used in a training set.

Anyone who has viewed all of the high affinity mu ligands will recognize that the paper earlier in this thread that describes and alpha and beta aromatic which is apparent in this case. Of course, the active conformation of this class is a little more difficult to find.

This is the article for Pipramadol/Pipradimadol.

 

[3DQSAR]

Sci-Hub | Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties. Journal of Medicinal Chemistry, 26(1), 42–50 | 10.1021/jm00355a010

I think I posted this link up a few months ago, we are duplicating our efforts here ;-)

I think I read recently that 2-halo substitution of the phenylethyl moiety of the fentanyl class resulted in more potent derivatives.

Tell me, did the researchers try protecting that bare hydroxyl? I only ask because with sulfentanil, Janssen disclosed that the methoxymethyl increased activity by an order of magnitude. It IS the : O : that increase affinity in that case rather than the group being a HBD but I don't know if that is the case here.

Do the two overlay closely?

Also, it turned out that the racemate was more potent than either of the two isomers. Now THAT is interesting. I think that is telling us something - possibly that the unbound conformation of the MOR might have two optical isomers. I know, I know, that's a HUGE leap of faith, but it's the sort of thing that is always worth bearing in mind. I have hundreds of little facts like that stored away and you know, over the decades I have found answers to some of them as science advances.

 

[4DQSAR]

Substituted Tetralins I: Synthesis and Analgesic Activities of Some 2-Aminotetralins

doi: 10.1021/jm00308a034.

Note the activity of compound IX.

Non-phenolic, synthetically simple and with an ED50 in animal models of 0.02mg/kg which compares favourably with pethidine (Demerol) which in the same model has en ED50 of 0.05mg/kg and codeine, again, 0.05Mg/Kg..

Not potent, but given the low cost of synthesis, a reasonable RC depending on it's subjective action.

What the paper DOESN'T cover is the fact that the compound is chiral and that it's almost certain that the (S) enantiomer is almost certainly responsible for all of the activity so if one could find an appropriate way to resolve the enantiomers, the unwanted isomer could possibly ber oxidized back to a ketone and then reductively aminated back to the raecemic product. Depending on the synthesis, if the N-monomethyl compound is produced, it could EASILY be raecemized and then methylated using the Einsweiler-Clarke reaction.

Going one step further, presuming the compound overlays the A & B rings of the morphine scaffold, it's possible that the para-phenyl piperadine or para phenyl piperizine derivatives (or indeed other aromatics) could theortically increase potency by x-4-8 (as N-phenylethyl moieties tend to do for morphinans or even by 12-24 by using a 2-thienyl as the aromatic ot even by as much as 24-48 using a 2-furanyl as the aromatic. BUT it has to be said that in many other classes, it's been shown that the 2-thienyl is the more active. Certainly the 2-furanyl seems to produce a huge varience in activity depending on the species used for the in vivo testing.