Quinaldine opioids

[paracelsius]

Opioids SAR never cease to amaze me:

this compound is neutral at physiological pH, lacking basic nitrogen and/or phenolic OH assumed to be required for opioids activity. Yet it is equipotent to M. Oh wait! maybe the 4-aminoquinaldine ring N gets protonated?? 4-aminopyridines pKa is pretty high may be same for 4-aminoquinaldines??
Some of the derivatives are actually quite potent (4-10xM).. Make no sense whatsover!!

 

[darvocet21]

It also makes no sense that heroin is considered a unique compound and not a prodrug for morphine

 

[S.J.B.]

Looks like the pKa is pretty close to 7, so a significant proportion should be protonated at physiological pH, even if it isn't the dominant species.

 

[izo]

yea, opioid sar is interesting, so many different scaffolds.

 

[izo]

It also makes no sense that heroin is considered a unique compound and not a prodrug for morphine

well there is 6-monoacetylmorphine, active on its own and more potent than morphine.

 

[darvocet21]

well there is 6-monoacetylmorphine, active on its own and more potent than morphine.

I did not know that can you furnish me a sample for further experimentation

 

[izo]

nothing i can do.

 

[paracelsius]

Looks like the pKa is pretty close to 7, so a significant proportion should be protonated at physiological pH, even if it isn't the dominant species.

Thanks for the link. I didnt know ChemAxon giving it free online. thought it was pay access. I use PyMol, Datawarrior sometimes ChemSketch and their ChemAxon extensions (like pKa computation ..etc) are all paying. Anyhow, yeah it looks like op compound is basic enough to do the job. It is still weird tho doesnt look like anything I came across in term of opioids scaffolds.

 

[Fertile]

2-[(2-methylquinolin-4-yl)amino]-N-phenylacetamide?

I cannot find a reference stating that it has 'opioid' activity. If it does, is it mu and/or delta and/or kappa and/or nop?

 

[S.J.B.]

2-[(2-methylquinolin-4-yl)amino]-N-phenylacetamide?

I cannot find a reference stating that it has 'opioid' activity. If it does, is it mu and/or delta and/or kappa and/or nop?

It seems to be an agonist at both mu and kappa. However, I couldn't find any data which would suggest it is equipotent to morphine in vivo. Where did you get that information, @paracelsius?

It also has antiparasitic activity.

 

[Fertile]

Synthesis and characterizations of novel quinoline derivatives having mixed ligand activities at the kappa and mu receptors: Potential therapeutic efficacy against morphine dependence - PubMed

Based on an established 3D pharmacophore, a series of quinoline derivatives were synthesized. The opioidergic properties of these compounds were determined by a competitive binding assay using (125)I-Dynorphine, (3)H-DAMGO and (125)I-DADLE for kappa, mu, and delta receptors, respectively...

pubmed.ncbi.nlm.nih.gov

You will note that it specifies 'affinity' and 'activity' but doesn't state if it's agonist, partial-agonist, silent agonist, inverse agonist or antagonist.

It appears to most closely overlay metofoline but as the paper suggests that it's possibly of use in treating opioid dependence, it seems unlikely to be a full agonist at the mu receptors.

Some months ago I produced a thread to which I added one or more novel mu agonists every day for weeks. I ASSUME it's still there, but I was surprised that people didn't take those lead compounds and develop them given that the patents & papers were included so their action was well defined.

When you consider it's synthetic complexity (ignore 1-step synthesis, the precursors aren't commercially available.

I did also hunt that their is a simple U-47700 homologue that is x23 M, no more complex to make and AFAIK would be at least as euphoric and would not show up on any standard drug test. Hin 2 - try overlaying prodine & U-47700. Now try overlaying allylprodine with the N-allyl homologue of U-47700 (U-93951) which Jacob Szmuszkovicz DID produce but didn't test.

The key is that the allyl groups overlay but whereas allylprodine has 4 enanthiomeras, the U-47700 derivative has just 2 isomers which is where the value of x23 comes from (I presume).

There is so much known but not explored, that might be the better option. Don't forget - U47700 can be made in 1 step. The more potent analogue in 3 steps.

 

[S.J.B.]

You will note that it specifies 'affinity' and 'activity' but doesn't state if it's agonist, partial-agonist, silent agonist, inverse agonist or antagonist.

Both κ- and μ-opioid receptor agonists and not antagonist’s causes transient activation on pERK in cultured cells within a few minutes of application. Receptor specific antagonists also inhibited such stimulatory effect on pERK by the opioid agonists. The above observations were applied in primary cultures of astrocytes with a view to determine the opioid agonistic or antagonistic property of the test compounds. Astrocyte cultures were treated with the test compounds for 10 min and pERK levels were estimated by western blotting analysis. Like the κ-opioid ligand, U50488H and the μ-specific ligand DAMGO (data not shown), all the tested compounds were able to stimulate ERK phophorylation (Fig. 2a, b and c). Stimulation of pERK1/2 level by the test compound was also sensitive to the opioid receptor antagonist naloxone (10 μM), which could effectively block the stimulation but by itself had no effect (Fig. 2a).

...all of the test compounds exhibited opioid agonistic properties with varying degree of interaction at the μ- and κ-opioid receptors.

 

[Fertile]

I have found out the hard way that just because something looks good in an in vitro model is barely of any value when considering it's in vivo action. If it's LogP or pKa aren't appropriate - they won't work in the human body.

AH-7921, MT-45, (R,R) viminol and many others turned out to be no fun at all. There was no good way of testing if a novel opioid was of value short of actually trying it. They ALL stopped opioid abstinence syndrome but were certainly not popular as RCs, Picking off affinity and action is very clever but doesn't seem to reflect subjective activity.

Who would have thought U-47700 would be so good? Nobody knew and Jacob (Szmuszkovicz) isn't alive to ask.

Even BDPC doesn't seem very popular. I suspect it's because N-demethylation (major metabolic pathway) yields a kappa agonist and so the experience wasn't great. Nice for 4 hours, nasty for 8 more. In that case, simply swapping the p-Br for a p-Me solves the issue as said methyl becomes major metabolic pathway. OK, now it only lasts for 4 hours (or so) BUT it's pretty euphoric.

Theory is all well and good - actually make the stuff and try it, that is the acid test.

 

[darvocet21]

nothing i can do.

The grad students test subjects aren't going to be happy to hear that

 

[Fertile]

It's the fact that even post-grad lecturers don't often admit it. I'm convinced it's so they keep an advantage over their students.

Don't forget - MOST medications do not have a subjective effect and so that issue doesn't come into it. That said, often the best medicine isn't chosen as the candidate if their is a possible patent infringement. THAT seems terrible to me. Quite a few medicines could have been a lot better BUT the makers seek the highest profit.... and so while efficacy is important, it merely has to be as good as or better than existing agents (in double-blind studies), it doesn't have to be the best possible.

Medication like rosiglitazone are good examples. It increases the incidence of heart attacks BUT it was licenced. WHY it causes heart attacks is known, but the better option infringed upon a patent and so it wasn't considered. There are even worse things. The Trovafloxacin story involves hundreds of kids dead, hundreds more suffering brain damage but the studies (carried out in Africa) were designed to compare the highest dose of trovafloxacin with a moderate dose of the alternative.... so it LOOKED good unless you read the papers closely.

I'm sure I don't need to go into thalidomide, aminorex (and other diet drugs) & many others.

Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature

There have been no studies of the patterns of post-marketing withdrawals of medicinal products to which adverse reactions have been attributed. We identified medicinal products that were withdrawn because of adverse drug reactions, examined the evidence ...

www.ncbi.nlm.nih.gov

I think rule 1 is that the designer should be the 'first into man' and indeed until the 1960s this was usual. But then their employers worried that their lead chemists might get injured or killed.... which is of course MUCH more important than some random innocent dying.

 

[paracelsius]

^You seem to be a little fired up about that compound. I mean read the OP carefully it just mentions the "weirdness" of opioids SAR. Theoretically (aka on paper) nothing more! and then you go on ranting trying to find a thousand reasons why it may (may!) be bad. But that is how the human mind works. It is called default mode network DMN mostly controlled by deep layer 7 cortical neurons. Incidentally activation of these by 5HT2a agonists like psilocybin helps thinking "outside the box" ie do not prejudge anything (read up on that!).

BTW: The logP and pKa you refer to (and other parameters you havent mention TSA, PSA relative PSA, # of rotatable bonds, H-bond donors/accecptors) they all look pretty good to me for a CNS compound. You should've mention metabolic stability because it is an anilide.. oh well..Besides if it reverses naloxone it got to cross BBB isnt it? .. Good'day all BLighters

 

[paracelsius]

It seems to be an agonist at both mu and kappa. However, I couldn't find any data which would suggest it is equipotent to morphine in vivo. Where did you get that information, @paracelsius?

Sorry I missed that one. The thread seems to have derailed & gone off topic. Actually if you look at the mu DAMGO assay (norway rat) IC50 OP compound=1.15nM (fig 1a in the paper). Morphine IC50 in the same assay (DAMGO, norway rat) IC50=1.13nM (on average, cf pubmed). So it is pretty much equipotent to morphine in that assay (mu-DAMGO displacement). But it may be different in vivo because of kappa/delta selectivity, pharmacokinetics, other targets..etc etc

I should’ve have clarify that. Was just surprised when I came across that compound. Looks so different from any opioid I've seen. But I am more into stimulants SAR. Anyway, keep in mind those guys were looking for opioid treatment not analgesics. So they have no reason to directly compare it to morphine.

 

[Valentine4]

You will note that it specifies 'affinity' and 'activity' but doesn't state if it's agonist, partial-agonist, silent agonist, inverse agonist or antagonist.

Excellent observation... potent antagonism would, well, suck. Sorry not very scientific, but true.

 

[paracelsius]

Yeah that compound CAS-762 (iirc) looks quite similar to both OP compound and the U- benzamides OPs. It is a full agonist at mu (but also NOP) with about 4-5X morphine potency. No data on kappa/delta tho which I suspect it may be active..well they claim it safer than morphine (less respiration depression..etc) but imo it is bulls..t! Pharmacology looks pretty much like morphine's at least in rats.. but ppl are not rats (most of them anywayl!!!).. oh btw that is silly (those guys published that paper two years before filing patent which make it utterly useless waste of money.. but oh well

 

[fastandbulbous]

As far as I can see, the SAR of opioids is straight out of Alice through the looking glass, so many different compound exhibit opioid activity.
There is a Ph.D. thesis, by an Indian guy, about DAT inhibitors etc. that is very interesting reading