Opiates/Opioids' affinity for each receptor, μ κ δ Lets build a table/chart!!!!

[endotropic]

Fentanyl

- μ - Mu = Affinity: .7nM Activity: ?

- κ - Kappa = Affinity: 84.8nM Activity: ?

- δ - Delta = Affinity: 152.7nM Activity: ?

I'll edit my post with the efficacy information later

Edit: what outcome are we using to determine activity? analgesic effect in people? GTPgammaS stimulation? AC inhibition? whatever we feel like?

 

[sekio]

ideally analgesic effect in humans/murine models, otherwise just be sure to note what kind of activity so things can be kind of comparable

 

[endotropic]

ideally analgesic effect in humans/murine models, otherwise just be sure to note what kind of activity so things can be kind of comparable

It could be very difficult, if not impossible, to find analgesic efficacy split up by receptor for each drug. All three receptors have some kind of analgesic effect, so to split it out like this you'd need to block 2/3 and chart analgesia at the remaining unblocked receptor. I'm not sure if anything like that has ever been done.

Looking for analgesic efficacy irrespective of receptor could be informative, but I'm not sure how that fits in with this table.

 

[Ektor]

It would be nice to have a sticky or something with all these opioid receptor datas.
I actually have no idea how the efficacy values i posted where calculated, i think they are derived Ki/EC50 but in the Effective Concentration 50 i dunno what exactly effective stands for, for what effect?

 

[endotropic]

It would be nice to have a sticky or something with all these opioid receptor datas.
I actually have no idea how the efficacy values i posted where calculated, i think they are derived Ki/EC50 but in the Effective Concentration 50 i dunno what exactly effective stands for, for what effect?

EC50 can describe any measure of efficacy, you can't tell without more info. GTPgammaS stimulation is the most common measure of efficacy at the receptor level, analgesic effect at the organism level.

 

[servo75]

Ok so I'm a complete newbie to pharmacology. First, thanks to the OP for the big list. The values you list are they Pi or KPi (I have no idea what the difference is other than there's a log relationship and that in one lower is stronger and the other higher is more potent)? I always thought that KPi was used the unit nM or do they both use that unit? The conversion pKi = -log(Ki) means that Ki must be a number between 0 & 1, otherwise pKi would be a negative number.

Incidentally does anyone have this info for Tianeptine/Stablon (or know where I can find it)? My ultimate goal is to compare Percocet, Oxycodone (same thing?), Kratom, Codeine, and Tianeptine, though I suspect different strains of Kratom will have different levels of alakloids, and thus slightly different Ki values.



Also I skimmed through the PDF given for Kratom and what few values I could find were listed in 8.73 pKI, not Ki. I just want to make sure I'm not mixing the two up.

 

[serotonin2A]

Ok so I'm a complete newbie to pharmacology. First, thanks to the OP for the big list. The values you list are they Pi or KPi (I have no idea what the difference is other than there's a log relationship and that in one lower is stronger and the other higher is more potent)? I always thought that KPi was used the unit nM or do they both use that unit? The conversion pKi = -log(Ki) means that Ki must be a number between 0 & 1, otherwise pKi would be a negative number.

Like you said, pKi is the inverse log of affinity. It is a useful transformation because it is easier to compare values on a log scale. pKi is a negative number, but is usually reported as -pKi so that the minus sign can be omitted.

Basically the whole number in the pKi value tells you how many leading digits there would be in the Ki in Moles/L. So a pKi of -9 means the Ki is in the nM range, ie 0.000000001 mole/L or 1 nM.

Incidentally does anyone have this info for Tianeptine/Stablon (or know where I can find it)? My ultimate goal is to compare Percocet, Oxycodone (same thing?), Kratom, Codeine, and Tianeptine, though I suspect different strains of Kratom will have different levels of alakloids, and thus slightly different Ki values.

The affinity should be measured for the pure alkaloids, not the plant, so the Ki is fixed. Binding studies are based on molar concentration, and there is no standardized definition for a mole of kratom. Sometimes binding studies will be performed with plant extracts, but that is a screening tool.

Also I skimmed through the PDF given for Kratom and what few values I could find were listed in 8.73 pKI, not Ki. I just want to make sure I'm not mixing the two up.

 

[farmacista]

heroin gets metabolized into morphine, 3 monoacetylmorhphine and 6 monoacetylmorphine, and 6-mam should be more potent than morphine

 

[Keif' Richards]

So the ideal opioid is the one with the highest affinity for that mu receptor?

 

[farmacista]

i'm note sure that the ideal opioid is the one with highest affinity for mu receptor...methadone has higher affinity than morphine but it's supposed to be less euphoric, i think...and it has almost no activity for kappa and delta opioid receptor

 

[serotonin2A]

So the ideal opioid is the one with the highest affinity for that mu receptor?

It depends on what you mean by "ideal". Are you thinking in terms of absolute potency, safety (e.g, amount of respiratory depression), abuse potential, or analgesic efficacy? Having high affinity for MOR doesn't necessarily mean that a compound will produce morphine-like effects, it also depends on its receptor efficacy, metabolism, and whether it can partition into the CNS.

 

[dopamimetic]

AH-7921
- Ki: μ = 10 nM / k = 150 nM (source on page 10)

Could be interesting to add the potency compared to morphine or equal dose to the table?

Also always thought the problems with buprenorphine (precipitated w/ds) were due to the delta/kappa antagonism, but as methadone is inactive at these receptors either, it seems likely that the relatively low mu-efficacy causes them?

 

[adder]

I started building such a table to find more detailed SAR, I managed to gather ~100 entries, however, it's not really so easy to compare affinities for different ligands. The affinity will largely depend on the radioligand and methods used, for instance if you use [3H]-DAMGO and [3H]-diprenorphine in two different experiments to measure morphine's affinity, you will obviously get different values. Naltrexone at DOP receptors has the affinity of 10.8 and 1.23 nM against [3H]-Cl-DPDPE and [3H]-DPDPE respectively, that's a huge difference. Also, if you want to compare affinities at different opioid receptors, then I guess it's best to use different radioligands for different receptors and each should have comparable affinity at its target.

Basically it's not enough to give the value, you also need the radioligand and method used to be able to compare affinities for different compounds.

 

[Keif' Richards]

Toucher. Well, I'm an addict so I didn't even take the time to debate the medical virtue of given opioids. For instance, I find hydromorphone to be the most euphoric opioid I've ever used. My favor for it could just be a result of it's relatively quick onset and rush, not so much it's receptor affinity. Heroin is my favorite only out of economy and the fact that it lasts longer. Also, I feel methadone is probably as euphoric/enjoyable as heroin/morphine, but, the protracted onset makes it less so...

So yea, which is most euphoric is my question really.

 

[dopamimetic]

Quick and full onset and the following rush -imo- are among the primary points of creating euphoria (above the mood lift coming just from the physical and psyhical painkilling/dulling), but probably also contribute to a quicker and/or stronger tolerance buildup. But don't know how much proven this is.

As a contrast, AH-7921 is a notoriously non-euphoric opioid, but it's a good pain-killer (physical but psychically too), lasts long to very long (24h+ with repeated dosing) and despite that long receptor agonism, it built way less tolerance in a way longer time than heroin. Have to say that I have been on memantine these days, which probably interfered with all (will post later about this).

 

[AlsoTapered]

Affinity ≠ efficacy

Etonitazene, tapentadol and tianeptine are all superagonists while buprenorphine, butorphanol and tramadol are all partial agonists.

I mention the above so people realize that drugs can lie anywhere from superagonist to agonist to partial agonist to silent agonist to inverse agonist to antagonist.

Both affinity and efficacy need to be considered along with some physical properties such as LogP.

 

[swimmingbird421]

THANK YOU OP.
Doing the food of the gods a favor.

So the lower the nM affinity the better binding?
I see codeines is a high nM and on the other side the scale hydromorphone s is much lower (.24nM)