What is potency? Why is x more potent than y?

[SpecialGuy69]

So, what is it about a specific opiate that makes it potent? We all know fentanyl is more potent than morphine. Buy WHY? Here's what I'm NOT talking about:
-ROA. Assuming all chemicals are administered IV, they all still have different potencies
-Metabolism. Codiene metabolizing to morphine isn't what I'm referring to.
-methyl group at the 3-position makes it more potent. Ok, we are getting somewhere, but WHY???

Before I really knew much about opiates, I used to think that one opiate was more potent than another because the molecule was smaller and lighter, thus there were more moles per gram (or, more molecules in each mg). So, if this were true, one mole of fentanyl would be as potent as one mole of morphine. Well, this is obviously not true.

What I'm thinking now is that a more potent opiate molecule is sturdier- it can activate more receptors before it is metabolized and degrades into an inactive (or less active) metabolite. Problem with this is "binding"- the whole concept of "blocking", as in subutex or buprenorphine blocking your high, relies on the principle that an opiate molecule stays on the receptor it activates.

So, anyone care to take a stab at this one?

[WarmCyanide]

my digging shows the relevence of concentrations of the drug.

i.e. codeine not a strong cuz it's synthesized from morphine. but then again so are dillies.

search continues...

i'm reading alot of shit on the web and it looks like theyre comparing x to y x to z z to y y to b etc. (letters referring to poppy derivative names.

still looking...

this link looks promising...

http://answers.yahoo.com/question/index?qid=20061204225258AAiVz6J

[SpecialGuy69]

I think the answer lies in a misconception a lot of us have: That opiate (mu) receptors are an on-off proposition, and there is no in-between. I think that one molecule of fentanyl "charges" a mu-receptor much more than a molecule of morphine.

For example, the fent molecule binds with a mu receptor, and causes it to release 80ug of chemical x, whereas if a morphine molecule binds to the same receptor, it only releases 1mg of chemical x. Therefore, fent is 80x stronger than morphine.

Chemical x being whatever causes the pleasurable opiate response in the brain. Endorphin?

[Levity]

I think the answer lies in a misconception a lot of us have: That opiate (mu) receptors are an on-off proposition, and there is no in-between. I think that one molecule of fentanyl "charges" a mu-receptor much more than a molecule of morphine.

For example, the fent molecule binds with a mu receptor, and causes it to release 80ug of chemical x, whereas if a morphine molecule binds to the same receptor, it only releases 1mg of chemical x. Therefore, fent is 80x stronger than morphine.

Chemical x being whatever causes the pleasurable opiate response in the brain. Endorphin?

It might bo be a chemical, it could just be an electrical impluse, a few molecule thick protien encoded with instructions to switch to on.

My two cents.

[mollywopped]

I asked this question on a different board because I thought it was interesting. Long story short, the better a chemical binds to opiate receptors, the more potent it will be. Fent has a higher mu-receptor binding affinity than morphine so it is more potent, ROA and dose being equal.

[SurfRat]

I asked this question on a different board because I thought it was interesting. Long story short, the better a chemical binds to opiate receptors, the more potent it will be. Fent has a higher mu-receptor binding affinity than morphine so it is more potent, ROA and dose being equal.


Yes that makes sense.

And with Heroin vs Morphine it has to do with Heroin being able to enter your brain (?) more efficiently so even though it turns into morphine, the molecule effects a more efficient delivery system, so you get more and faster with Heroin than you ever could with morphine. (I think that's how it works, I was puzzling over it for a long time...)

[SuperJunky]

I asked this question on a different board because I thought it was interesting. Long story short, the better a chemical binds to opiate receptors, the more potent it will be. Fent has a higher mu-receptor binding affinity than morphine so it is more potent, ROA and dose being equal.
Not necesarily true, buprenorphine has a higher affinity than say morphine, and while it requires a much smaller dose, it doesn't produce the same effect as say an equivalent dose of morphine would...

*EDIT* That really didn't get my point across, on the off chance some one gets what I'm trying to say I'll leave it, other wise wait till I rethink it and repost before ripping this apart.

[robojunkie]

I'm in a hurry, will add more later, but there are some basic considerations. First is the affinity for the mu opioid receptor. Note affinity has nothing to do with potency, as naloxone can and does have a greater affinity for the MOR than oxycodone or morphine or even heroin. Second is the overall hydrophobicity or as stated in medical texts as a simple way to represent it, the octanol/water partition coefficient. Thirdly is the overall relationship of the molecule (by way of its size, shape, polarities, and so forth) and how this affects not the affinity but the activation of the MOR. So in short, affinity only means how well and how long overall that the substance binds to the MOR, and can be expressed in terms of an IC-50, which I forget the words to, but is an expression of how well a substrate binds to an enzyme or receptor, and nothing else (not stimulates, etc) and activity refers to how well it stimulates the receptor once it is "docked". And, finally, the third thing,the molecular traits of shape and size (sterics), polarity (electrostatics) and lipophilicity (opposite of hyrophilicity, can be used interchangeably with hydrophobicity), relates strongly to both affinity and to activity.

OK, I will make this more clear with examples in a couple of hours.

[SpecialGuy69]

It seems to be that the most important thing to understand is that receptors are not a simple on/off proposition, where on=high and off=not high. naloxone illustrates this point well- the receptors are bound to the nalox, but you sure as hell ain't high.

So, once a molecule binds to the receptor, certain things affect how much it is activated, and for how long. The factors that RJ listed- shape of molecule, stability, polarity, etc; determine this.

This is all assuming that the molecules are already past the bbb (blood brain barrier). Another factor in potency is what % of the molecules survive the trip to the brain intact (or as active metabolites). We are always trying to figure out how to slip loperdamide past the bbb unspoiled. I say you need more astroglide.

The water/octanol thing is interesting, too

fascinated to hear more on the subject, RJ, cant wait!

[mollywopped]

Not necesarily true, buprenorphine has a higher affinity than say morphine, and while it requires a much smaller dose, it doesn't produce the same effect as say an equivalent dose of morphine would...

*EDIT* That really didn't get my point across, on the off chance some one gets what I'm trying to say I'll leave it, other wise wait till I rethink it and repost before ripping this apart.


Hey, I have no idea, I was just telling you what was explained when I asked this question somewhere else. I found this question interesting, but it didn't really get any answers over here so I aksed it somewhere else.

I am not a chemistry guy. I would rather fuck a cactus than have to do any math, which is the reason I majored in Poli Sci and history, about as far from math as you can get.

So if someone can explain this in laymen's terms, it would be appreciated.

As for Bupe having a higher affinity than morphine, that may be true, which is why bupe works at 2mg doses but morphine requires more. I don't think potency has anything to do with euphoria, which is kind of the impression O got from the bupe example a few posts up. But, like I said, I not proficient by any means in chem, so I may have totally misunderstood that example.

[robojunkie]

OK so first, just addressing the receptor, ligand (drug or endorphin/enkephalin in this case), and the brain, and forgetting about the other stuff (like the BBB as this will confuse it more), the best way I can think of to explain it in laymen's terms is an extension of the old lock and key metaphor.

First, obviously let's think of the drug as the key and the receptor as the lock. But to make it a more accurate example we need to really picture keys and locks (if I could draw diagrams and speak chem I'd do it but I can't). The metaphor also continues with the lock being opened and therefore the door as well, this being representative of a true opioid agonist.

But, let's take some random keys, all of them the bronze Schlage keys. We have a door, and to this door, 4 out of 5 fit the lock. The one not fitting is an example of a non opioid substance, neither ag or antag or mixed, just nothing to do with it. However the other four are part of one of the above groups and have an affinity for the receptor (they fit in it). (and to make it more accurate imagine that they are magnetized some more than others, and this makes them stick more and harder to remove). As we first notice how quick they go in and how hard they are to remove, we have now measured their "IC-50s" which is representative of a substance's affinity for a given receptor (MOR/lock). And all being schlage keys, they all have some very specific structural (spatial, really) arrangements in common. It is this that is primarily responsible along with the magnetism (like the areas of polarity and oiliness or hydrophobicity and hydrofilicity) that makes up a drug's affinity profile.

However, with the 4 keys in place, we note that only two open the door, even though all four went in. The two that didn't open the door, one a weak magnet the other very strong, are antagonists. They fit (and fill) the receptor, however due to the fact that a receptors overall shape and polarity is responsible mainly for affinity, whereas specific areas of shape and polarity are reposible for agonism, these only fit but don't open, because the gratings on the key just don't match the particular areas that need to be "hit". So the two keys block the door from being opened with the others, and one is much harder to remove (magnet) than the other, making it a much stronger anagonist.

Now, we take one of the "working" keys, and open the door. We notice that it fit quite well, and additionally had the appropriate gratings (like the right functional groups on the right place of the molecule) and as such had good affinity and good activity. However, even though it was also highly magnetized, its match up with the gratings fittings in the lock was OK, but not perfect. So in opening the door lots of jiggling and twisting had to be done. In doing this the constant shifting of the key doesn't allow for 100% stimulation of the receptor. Due to this, it is a mixed agonist/antagonist, with very strong affinity but a weaker incomplete activation profile. The "magnetization" increases both properties, but the match up of gratings (measured as some number we'll make up) isn't perfect, enough to open the lock, but not enough that some of the lock gratings were ignored, and with a good enough fit (affinity) to prevent pure agonists from "hitting".

Finally the last key, which just happens to be a moderate magnet, is pushed in, and as it enters completely, the lock turns like a well oiled dropper. Every single fit in the lock matches perfectly with the key gratings, and all active sites on the receptor (lock) are fully stimulated. So this key, with moderate affinity (say like morphine) but with a perfect arrangement of functional groups (key gratings) behaves as a pure agonist. Its overall potency is a function of its magnetic key strength, as well as the "magnetic" effects of each grating and fit together. As an example, if this key was the strongest magnet overall and the gratings with their little magnets matched perfectly with the receptor's/lock's fits, we'd have carfentanil or etorphine. It they fit well but was a weak magnet we'd probably have demerol.

The sencond example would be like buprenorphine or talwin, the first would be naloxone (weaker magnet) or diprenorphine (stronger magnet, a pure antagonist analogous to etorphine in affinity) as antagonists. The last of course is morphine, heroin, methadone, fentanyl, oxymorphone, etc.

Does this make sense to everyone? If I could "draw" little diagrams I could explain it much better by drawing these interactions as real molecules and fitting them on paper.

[SpecialGuy69]

Wow! Great answer and explanation!
</p>
So then it would be easier to design an antagonist, then a mixed ag/antag, and most difficult (most specific) would be an agonist? Do antagonists follow the morphine rules? (i.e. - A phenyl or aromatic ring -quaternary carbon atom -CH2-CH2 group -The CH2-CH2 group must be attached to a tertiary nitrogen atom.)

[Nate]

^^Indeed, well said Robo, thanks bro.

[RxQueen]

excellent explanation, RJ! can everyone see the glare of the lightbulb that just turned on over my head? :D

[Nate]

excellent explanation, RJ! can everyone see the glare of the lightbulb that just turned on over my head? :D

Yeah, turn it off, it's blinding me. :D

[CIIORNOTHING]

The precise mechanism of action of all analgesics is unknown, and it states this in most package inserts and other detailed documents. So researchers, doctors and scientists dont have a clear understanding of all of it, and doubtful that anyone here will :) (though we do have smart SOBs here).



Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis).
The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.

[SpecialGuy69]

The precise mechanism of action of all analgesics is unknown, and it states this in most package inserts and other detailed documents. So researchers, doctors and scientists dont have a clear understanding of all of it, and doubtful that anyone here will :) (though we do have smart SOBs here).



Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis).
The precise mechanism of the analgesic action is unknown. However, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.

read RJs post above- does a good job explaining what IS known.

[CIIORNOTHING]

read RJs post above- does a good job explaining what IS known.


Yes, absolutely, that was excellent. But the answer as to why one may have higher affinity for the mu receptor, but not be as potent to the patient, I beleive is part of that unknown mechanism stuff they talk about.

[robojunkie]

Wow! Great answer and explanation!
</p>
So then it would be easier to design an antagonist, then a mixed ag/antag, and most difficult (most specific) would be an agonist? Do antagonists follow the morphine rules? (i.e. - A phenyl or aromatic ring -quaternary carbon atom -CH2-CH2 group -The CH2-CH2 group must be attached to a tertiary nitrogen atom.)

Well, the morphine rule is really more of a guide insofar as the above description is concernned. The above is the morphine rule (plus tertiary N must have a methyl, ethyl or phenethyl), and it IMO, is better thought of as a conformational rule, not a connectivity rule. So any substance like say enkephalins, etonitazine, fentanyls, and of course endorphins and some others that completely break the rule in one or more ways, may in fact when in the brain at that pH and solution, take on a conformation that places the important groups in the right places.

The precise mechanism of action of all analgesics is unknown, and it states this in most package inserts and other detailed documents. So researchers, doctors and scientists dont have a clear understanding of all of it, and doubtful that anyone here will :) (though we do have smart SOBs here).

Yes, absolutely, that was excellent. But the answer as to why one may have higher affinity for the mu receptor, but not be as potent to the patient, I beleive is part of that unknown mechanism stuff they talk about.

Yes, all that insert stuff is just pharmaceutical CYA junk so they can't ever be accused of making a mistake in their explanation. Do we know what goes on within the neuron, after the receptor, and on through the microtubule to the next synapse, where our consciousness' arise? No, and we won't until we know the "mechanism" of consciousness and why those receptors when stimulated provide euphoria and analgesia. However, we do very much know to a very precise level the chemical mechanism of action, what makes an opioid have a strong or weak affinity (phenyl or other aromatic ring, non-polar site with small area of polarity (only comes into play with the Bentley compounds), and the activity and type, generally centered around the perpendicular piperidine moiety, with N-methyl, ethyl or phenyl giving pure agonists, methyl and phenethyl usually being the strongest, and N-cyclopropylmethyl, allyl, cyclobutylmethyl and so forth. This is a simplification, as very precise spacial arrangements affect the potency of a given agonist or mixed ag/antag, and there are even other effects like the solvent environment and pH and so forth. In other words, lets say you could "magically" stretch the two bonds in morphine that form the piperidine ring, ie at the 4a and (13 or 15, I forget, one of them equals 4a), but left everything else the same. Even with say the two bonds being "stretched" by say 0.5 angstroms, without any other structural or conformational changes, will have a potency effect, either stronger or weaker, but very unlikely the same.

So, in short we know a huge amount about all of this stuff, hell the MOR "G-coupled protein" has been crystallized and an X-ray structure proposed and widely accepted, and not only that but the active site has been mapped out and I also believe that a bound MOR with fentanyl coupled receptor/ligand system has also been crystallized and X-rayed, with this structure showing the slight changes in the tertiary structure (the ribbons and curls and where they are in protein drawings) that result from binding and activating the receptor. And of course we know all the structures with precise bond lengths and angles as well as electronegativity (polarity) of particular areas, likewise with the receptor as well. So a huge amount is known about "the mechanism of action" at the synapse locality where the receptor and ligand (drug or hormone) reside. Its the stuff "down the line" in the actual neuronal interior that we don't know much about, where the secrets to "why" we feel these like we do, how this internal effect initiates tolerance and addiction, and in my opinion the key to developing substances capable of crossing into the neuron and disabling the enzymatic system within it that responds to "chronic" MOR stimulation with the traits of tolerance. This much occur somehow, and within the cell, and therefore I believe with little doubt that one day we can find a way to block these enzymes with a co-administered drug, which "tricks" the neuronal interior into believing the MOR is unoccupied when it is, in fact, all jammed up as they say!

[CIIORNOTHING]

Its the stuff "down the line" in the actual neuronal interior that we don't know much about, where the secrets to "why" we feel these like we do


Yep.

[Raz]

OK so first, just addressing the receptor, ligand (drug or endorphin/enkephalin in this case), and the brain, and forgetting about the other stuff (like the BBB as this will confuse it more), the best way I can think of to explain it in laymen's terms is an extension of the old lock and key metaphor.

First, obviously let's think of the drug as the key and the receptor as the lock. But to make it a more accurate example we need to really picture keys and locks (if I could draw diagrams and speak chem I'd do it but I can't). The metaphor also continues with the lock being opened and therefore the door as well, this being representative of a true opioid agonist.

But, let's take some random keys, all of them the bronze Schlage keys. We have a door, and to this door, 4 out of 5 fit the lock. The one not fitting is an example of a non opioid substance, neither ag or antag or mixed, just nothing to do with it. However the other four are part of one of the above groups and have an affinity for the receptor (they fit in it). (and to make it more accurate imagine that they are magnetized some more than others, and this makes them stick more and harder to remove). As we first notice how quick they go in and how hard they are to remove, we have now measured their "IC-50s" which is representative of a substance's affinity for a given receptor (MOR/lock). And all being schlage keys, they all have some very specific structural (spatial, really) arrangements in common. It is this that is primarily responsible along with the magnetism (like the areas of polarity and oiliness or hydrophobicity and hydrofilicity) that makes up a drug's affinity profile.

However, with the 4 keys in place, we note that only two open the door, even though all four went in. The two that didn't open the door, one a weak magnet the other very strong, are antagonists. They fit (and fill) the receptor, however due to the fact that a receptors overall shape and polarity is responsible mainly for affinity, whereas specific areas of shape and polarity are reposible for agonism, these only fit but don't open, because the gratings on the key just don't match the particular areas that need to be "hit". So the two keys block the door from being opened with the others, and one is much harder to remove (magnet) than the other, making it a much stronger anagonist.

Now, we take one of the "working" keys, and open the door. We notice that it fit quite well, and additionally had the appropriate gratings (like the right functional groups on the right place of the molecule) and as such had good affinity and good activity. However, even though it was also highly magnetized, its match up with the gratings fittings in the lock was OK, but not perfect. So in opening the door lots of jiggling and twisting had to be done. In doing this the constant shifting of the key doesn't allow for 100% stimulation of the receptor. Due to this, it is a mixed agonist/antagonist, with very strong affinity but a weaker incomplete activation profile. The "magnetization" increases both properties, but the match up of gratings (measured as some number we'll make up) isn't perfect, enough to open the lock, but not enough that some of the lock gratings were ignored, and with a good enough fit (affinity) to prevent pure agonists from "hitting".

Finally the last key, which just happens to be a moderate magnet, is pushed in, and as it enters completely, the lock turns like a well oiled dropper. Every single fit in the lock matches perfectly with the key gratings, and all active sites on the receptor (lock) are fully stimulated. So this key, with moderate affinity (say like morphine) but with a perfect arrangement of functional groups (key gratings) behaves as a pure agonist. Its overall potency is a function of its magnetic key strength, as well as the "magnetic" effects of each grating and fit together. As an example, if this key was the strongest magnet overall and the gratings with their little magnets matched perfectly with the receptor's/lock's fits, we'd have carfentanil or etorphine. It they fit well but was a weak magnet we'd probably have demerol.

The sencond example would be like buprenorphine or talwin, the first would be naloxone (weaker magnet) or diprenorphine (stronger magnet, a pure antagonist analogous to etorphine in affinity) as antagonists. The last of course is morphine, heroin, methadone, fentanyl, oxymorphone, etc.

Does this make sense to everyone? If I could "draw" little diagrams I could explain it much better by drawing these interactions as real molecules and fitting them on paper.

Cor, fuck a duck!!.Even i understood this one....Word perfeck,nice one R J....

[CIIORNOTHING]

Cor, fuck a duck!!.Even i understood this one....Word perfeck,nice one RB....


liar. no you didnt. :)

The question asked back there was why we feel some more than others. You can talk receptors and synapses all day, but his/her statement above about not knowing the down the line stuff and why we feel what we feel is what I was getting at. But I think its quite clear that robo is the resident expert on this LOL!

[OxyContinuously]

potency is relative...in other words, u must have something to compare the specific substance to..

otherwise it is meaningless

in the medical community, a lot of times, morphine is the "gold standard" so potency is measured relative to morphine

so chemical X may or may not be stronger than morphine, for example.

but that's how they gauge it-- u have a standard and compare the rest of the opiates to that standard

[roxi*stardust]

Nice simple explanation robo. Now here's one for you. Take methadone for example. My understanding of it's length of action and longer come on effect is because of it's size. It is larger than other molecules (opiates) so it squeezes itself into the receptors causing it to take longer before you feel the effects. The same applies when it leaves the receptor, it leaves more slowly because of it's size causing a prolonged effect. Bupe works differently because it just has a stronger attraction to the receptors, rather than a being larger than the receptor site. Is this right?

[robojunkie]

Nice simple explanation robo. Now here's one for you. Take methadone for example. My understanding of it's length of action and longer come on effect is because of it's size. It is larger than other molecules (opiates) so it squeezes itself into the receptors causing it to take longer before you feel the effects. The same applies when it leaves the receptor, it leaves more slowly because of it's size causing a prolonged effect. Bupe works differently because it just has a stronger attraction to the receptors, rather than a being larger than the receptor site. Is this right?

Damn, I gotta get myself a copy of my own chemdraw program so I can draw this stuff out, It's so much easier to explain/understand with the pictures. As far as methadones length of action, I've always understood this to be a function of its relatively small amount of functionality and its relatively high lipophilicity. So, because of the functionality thing the liver has less sites on which to act in metabolic transformations, and the "oily" thing generally keeps in in the area of fattier tissue in greater relative amounts and for greater relative time periods. As for its slower come on, I haven't read any specifics, and I know it isn't a pro-drug, so that's ruled out. But I think it is quite possible that, not exactly because of size so much as an "open" (aliphatic) piperidine moiety, when it approaches the receptor, and (presumably) the pi-stacking effects of the phenyl rings initiate some binding, and at this point the open chain, which isn't going to bind or activate in that conformation, through random molecular twisting and bending, takes on a conformation with the chain arranged like a piperidine moiety with an "invisible" bond. Even though this is energetically less favorable (entropy goes down), this conformation is the only one that will bind with the active site, thereby momentarily "freezing" it (momentarily probably means time spans less than milliseconds) in that conformation.

As far as lifetime at the receptor itself, I don't think this is generally related to its duration of action. As I understand it, anytime a ligand (that doesn't bind irreversibly, that is chemically react with the receptor) binds and activates a receptor, slight tertiary structure changes occur, and this both stimulates a change in the cross membrane potential down the microtubules and this reaches a threshold and releases its energy as an electrical signal down the tubule to the next synapse, releasing whatever transmitters there. But a second effect of this tertiary structure change is the temporary alteration of the binding site's characteristics, which causes the ligand to "fall off". It is also helpful to try and visualize these things not as big "molecule" models like on PBS specials, but as various shapes and so forth moving extremely fast and constantly banging into each other and changing shapes and so forth far faster than we could visualize.

As for bupe, my understanding of its "odd" (mixed partial ag/antag) characteristics is that first, the side chain that it has in common (w/ a slight difference) with etorphine, actually hugely increases its binding affinity, not as a function of size, but of positive electrostatic interactions (the receptor with say morphine, isn't entirely filled, this area of binding is just not interacted with). Primarily, I believe the fact that it is not a pure agonist is almost entirely a function of its N-cyclopropyl group, which due to its size and shape (sterics), prevents full (and in some cases any) stimulation of the active site. Other than this, the only difference between it and etorphine is the hydrogenated "etheno bridge" which I doubt has much effect on affinity or ag/antag character and the "methyl-t-butylhydroxymethyl" side chain (etorphine just has a "methyl-n-propylhydroxymethyl" side chain).

So generally I don't think it is size per se, after all fentanyl is a quite long molecule, with the N-phenethylpiperidinyl-phenyl propionamide structure, thats three rings, with an ethyl in between two and an N ibetween two. However, fentanyl happens to have all the right rings and distances, and since it isn't totally "locked" into shape like morphine, is free to rotate and spin to best fit the active site as well as the general binding site.

[SpecialGuy69]

rj- a couple of things you said confused my retarded chemistry mind.

You were speaking of the piperidine moiety of methadone, but I dont see any piperidine rings in it. In fact, I only see one nitrogen at all, but it is single bonded to three carbons (amine?). What gives (I'm sure I'm missing the definitition of piperidine moiety here)

Also- when a 6 carbon ring is flat, its called a benzene, and its also an aromatic ring.

Are all aromatic rings flat and all cyclo- rings chair or boat shaped? Is that how they draw the distinction between the two?

[robojunkie]

rj- a couple of things you said confused my retarded chemistry mind.

You were speaking of the piperidine moiety of methadone, but I dont see any piperidine rings in it. In fact, I only see one nitrogen at all, but it is single bonded to three carbons (amine?). What gives (I'm sure I'm missing the definitition of piperidine moiety here)

Also- when a 6 carbon ring is flat, its called a benzene, and its also an aromatic ring.

Are all aromatic rings flat and all cyclo- rings chair or boat shaped? Is that how they draw the distinction between the two?

OK, first the reason I say piperidine "moiety" is that this would include, in addition to an actual piperidine ring, something that is free to conform itself in that "shape". The "6-dimethylamino-3-heptanone" part of done, the straight chain in other words, can bend itself around so that the quarternary carbon (mentally) would be the same as the one in morphine, the chain side with the amine is the one coming "out" of the page, with one methyl being the "N-methyl" and the other being another piece of the "moiety" (and the last methyl of the chain would represent the 10 postition, the ring in "back" on morphine that connects back to the aromatic one. The other part of the chain with the ketone, this is the part that would represent, in morphine, the part of the piperidine moiety that goes "back", with the ketone kinda being the one double bond ring beginning and the rest finishing the back of the piperidine moiety. If you have a model or if you draw morphine, then draw methadone as best you can in the exact same configuration, it'll be easy to see what I mean.

Generally speaking you are correct. All, and I mean all, aromatic rings to my knowledge are flat. This is one of several requirements for a molecule to have "aromaticity". The flatness allows all the p-orbitals to line up perfectly to make 6 molecular orbitals. Draw a benzene with a point down annd up, then draw a "diagram" with a line where every carbon is (not on top of it) and fill each line with the six electrons starting at the bottom. (This means two arrows for each, one up, one down.) You'll notice that you perfectly fill the bottom three, with the last two filled (and first two unfilled) being parallel, or having the same energy (you have to fill "same energies" one by one, not two electrons in one and none in the other).

This is why they are very stable, and this is also why something like cyclobutadiene, with two double bonds in the same "on-off" arrangement like benzene is antiaromatic. Draw this point down and up and do the same thing with its four electrons. You'll see that the parallel two orbitals can only have one electron each, making it a "triplet state" and a diradical, which is extremely unstable (it in fact has never been successfully made as is, only with a bunch of t-butyl groups in frozen argon). So in short yes all aromatic rings, including heterocycles like indole, pyrrole, furan, etc, are all flat because this allows the orbitals to line up perfectly with all six electrons. (By the way, the same "lines" model works if you use it for five membered aromatic heterocycles, drawn with point down, edge up).

And yes, all of the "cyclo" coumpounds imply 1) that there is a ring (no shit, right?) and 2) that they are not aromatic rings (nor are they "anti-aromatic" rings. There properties are much more like their straight chain cousins). There are some other freaky examples of "semi-aromaticity", like the (in)famous norbornene cation (I say this because these two chemists fueded for years, insulting each other in articles throughout the fifties because they disagreed about this), which has an aromatic property where three p orbitals, with only 2 electrons, are all in a circle, even though they are not on carbons bound to each other. But the configuration is so stabilizing that an anion (nucleophile) can only attack from the "top" where the orbitals aren't as aligned. Sorry, its hard to explain without a fucking draw program. Maybe just for fun I'll post it here when I get back to school/work (I just picked up my family and came in to check on the old 'phile...). Anyways...

[resorcinol]

I think the answer lies in a misconception a lot of us have: That opiate (mu) receptors are an on-off proposition, and there is no in-between. I think that one molecule of fentanyl "charges" a mu-receptor much more than a molecule of morphine.

For example, the fent molecule binds with a mu receptor, and causes it to release 80ug of chemical x, whereas if a morphine molecule binds to the same receptor, it only releases 1mg of chemical x. Therefore, fent is 80x stronger than morphine.

Chemical x being whatever causes the pleasurable opiate response in the brain. Endorphin?

Coordination chemistry helps in understanding this. It has to do with where the equilibrium of the reaction to form the u-receptor-ligand complex lies, ie, it's a reversible reaction that continuously proceeds both ways. When as much unbinding occurs as binding, it's at equilibrium. If this happens with the reaction shifted towards the complex, ie more opiates are binded than not when equilibrium is reached, you've got a more potent compound than one with an opiate that has it's equilibrium shifted towards the separate opiate and u receptor.

Generally the forward reaction in medicine is actually considered the UNbinding of a drug, so you want the reverse reaction to be favored, forming the complex. So, the lower the equilibrium constant for a particular opiate and the u-receptor, the more potent the drug. a drug with an Eq = 0.8 is weaker than a drug with an Eq = 0.4, for example.

Hope that made sense, I can have a hard time transferring my understanding into words sometimes.

EDIT: Anology :)

Imagine you have a room and a hallway. People are the opiates, and being inside the room is binding to the u-receptor. Imagine you have 100 people inside the room for drug A, and 50 people in the hallway, with two going out and coming in every second. This is equilibrium, the reaction continues, but the number in the hall and room stay the same at a given concentration of total people.

FOr drug B, 80 people are in the room and 70 in the hall, and two enter and two leave each second. once again, the reaction continues, but the number in the hall and room stays the same. this time though, the room isn't quite as favored as with drug A at this given concetration of 150 total People (molecules). Drug B would be weaker.

This is simplified and doesn't consider receptor density or a number of other things, but it can help understanding anyway. i'm holding receptor density and number constant for drug A and B.

[resorcinol]

For the most part opiate receptors ARE either ON or OFF. Potency has to do with how strongly and agonist favors binding the receptor and turning it ON like I described above.

Where the Eq lies has to do with the exact shape and bonding in the molecules.

[SpecialGuy69]

I wonder if there could ever be a way to cut out stimulating the u receptor altogether. Think like this- when the receptor is activated with an opiate molecule, it releases chemical x, y, and z (probably endorphin, dopamine, etc). Well, what if there was a way to just introduce chemical x, y, and z to the brain directly?

If different chemicals released by the u receptor are responsible for different aspects of the drug's effects, its possible that you could select which you introduced. For example:
chemical x is responsibe mostly for euphoria
chemical y is responsible mostly for itching and sleepiness
chemical z is responsible mostly for constipation and nausea

So in this example, chemical x would be the bad-ass one you'd want. I'm sure these chemicals are extremely complex long-chain polypeptides and would be too fragile for oral administration, but they could possibly survive IV administration, pass the bbb, and make you feel awesome.

Also- if a chemical cannot pass the BBB intact, would it become active if it was directly introduced into the brain (an injection through the skull, i.e.). Obviously there would be insurmountable health and safety risks to this, but I'm just curious if introducing a chemical directly to the brain would bypass the BBB altogether.
Imagine- junkys loading up a 30g rig with a 2" needle and shooting immodium directly into their brain through the temple. Talk about a dangerous abscess!

[stvip]

For the most part opiate receptors ARE either ON or OFF.

Not really. The distinction between the Gi vs. Go (or Gs) signal transduction of the opioid receptor seems to have much to do with opioid tolerance.

[resorcinol]

Not really. The distinction between the Gi vs. Go (or Gs) signal transduction of the opioid receptor seems to have much to do with opioid tolerance.

That's tolerance.

What I meant is as far as a ligand binding the receptor goes. A fent and u receptor complex and a morphine and u receptor complex cause the same changes in the u receptor, fent is just more likely to for the complex at lower concentrations.

[stvip]

What I meant is as far as a ligand binding the receptor goes. A fent and u receptor complex and a morphine and u receptor complex cause the same changes in the u receptor

No no - that's false as well. In fact, morphine in particular seems to affect receptors differently than most other opioids, but also in general, different opioids can bind differently to the receptors and cause different signal transductions.

[resorcinol]

No no - that's false as well. In fact, morphine in particular seems to affect receptors differently than most other opioids, but also in general, different opioids can bind differently to the receptors and cause different signal transductions.

Not sure I buy that. Show me some studies and I'll come around.

not tryin to be a pain I just want proof.

what i said about equilibrium is the primary factor in drug potency though

[stvip]

Not sure I buy that. Show me some studies and I'll come around.

not tryin to be a pain I just want proof.

An obvious example is the differences in the propensity to cause receptor internalization by different ligands.

Or have a look at these (I'm putting links to the articles rather than typing journal citations):

http://www.ncbi.nlm.nih.gov/pubmed/9351981

http://www.ncbi.nlm.nih.gov/pubmed/17152090

Especially interesting is http://jpet.aspetjournals.org/cgi/content/abstract/jpet.102.046219v1

From The FASEB Journal. 2001;15:598-611:

There are still other lines of evidence to suggest that agonists produce ligand-specific receptor conformations. Selective mutations of dopamine D2 receptors caused selective abolition of receptor/G-protein activation by dopamine but not other dopamine agonists. This suggests that these agonists produce different receptor conformations interacting with G-protein (98) . Studies of the receptor desensitizing effects of different agonists also indicate the production of ligand-specific receptor conformations. For example, it would be expected that the relative propensity of agonists to induce desensitization would parallel their relative efficacies. This was shown to be generally true for µ opioid receptor agonists, with the notable exception of methadone and L-http://www.fasebj.org/math/agr.gif-acetyl methadone. These latter agonists produced disproportionate desensitization and receptor phosphorylation, suggesting different receptor conformational changes (99) . Similarly, methadone and buprenorphine have been shown to demonstrate different desensitizing properties from morphine on µ opioid receptors (100) . In other studies of recovery from desensitization, it has been shown that agonists appear to produce different conformations. Thus, whereas the recovery from prolonged activation of 5-HT3 receptor with partial agonists is mono-exponential, it is sigmoidal (indicating 3 steps and 4 states) with full agonists (101) .
The effects of agonists on receptor internalization also have furnished interesting data regarding ligand-specific receptor conformation. Here it can clearly be shown that the simple strength of receptor stimulation can be differentiated from the ability of ligands to induce receptor internalization. For example, the cholecystokinin (CCK) receptor antagonist D-Tyr-Gly-[(Nle28,31,D-Trp30)cholecystokinin-26–32]-phenethylester does not produce receptor stimulation but rather blocks CCK responses. This antagonist also produces profound receptor internalization (102) . Similarly, whereas enkephalins and morphine produce stimulation of http://www.fasebj.org/math/dgr.gif and µ opioid receptors, enkephalins induce rapid receptor internalization whereas morphine does not (103) . These data indicate that the conformations that lead to response are not necessarily the same as those that induce receptor internalization. It also suggests that different agonists produce receptor conformations with differential propensity to internalize.


By the way, the reason I'm bothering with writing this is that I hope to convey the message that the opioid system is extremely complex, is far from being well-understood, and that much of information given to amateur audiences is grossly simplified, and often inaccurate (for example, the explanation given for the higher potency of diamorphine compared to morphine when given intravenously, that of the former being more lipophilic, is probably false, etc).

[robojunkie]

By the way, the reason I'm bothering with writing this is that I hope to convey the message that the opioid system is extremely complex, is far from being well-understood, and that much of information given to amateur audiences is grossly simplified, and often inaccurate (for example, the explanation given for the higher potency of diamorphine compared to morphine when given intravenously, that of the former being more lipophilic, is probably false, etc).

Yes the opiate system is very complex, and as far as tertiary structure of the MOR, naturally different agonists will cause slightly different overall shape (conformational) changes, but nonetheless, one can peruse endless peer reviewed articles on the opioid receptor system and read hundreds, even thousands of publications on it, and the end result is the same, that agonism requires "activation" (whether it be via H-bonding at a particular AA, or pi-stacking or a number of van der Waals interactions) and that in particular, this characteristic is common amongst all agonists. The antagonist, and more importantly the so-called "mixed partial agonist/antagonist" is the more precise example of a ligand type that has "unusual" activity as a result of its inability to confer the necessary changes in tertiary structure to cause an action potential to be reached internally. But with the full agonist, it is its relative concentration at the receptor (as opposed to serum levels, etc) that is by far the most important determining effect regarding its potency. Something is either an agonist, or it is something else, be it a mixed or a pure antagonist.

Tolerance development, on the other hand, seems to be a far more complicated phenomenon. Yes, methadone and morphine for example, provoke very different secondary responses as a result of their "constant" presence at the receptor, but whether by internalization and presumably lysing of the peptide structure, or external inhibition via some other mechanism, the concept of tolerance still does not seem to really vary all that significantly. After all, if internalization as the means of morphine tolerance were an important difference, than why such rapid tolerance build up to it (and heroin) as well as others like the fentanyls or methadone? I don't know why, nor do I think anyone has the "whole picture" on this yet, as if someone did as of yet, I have virtually no doubt that this would begin the era of real meaningful research on powerful tolerance and addiction process inhibiting substances, an area that I would be up all night writing grant proposals to fund my efforts in this future time. (This is something, BTW, that I have no doubt is an inevitability as logic says that tolerance to a drug effect, caused by the interaction between chemicals, be they simple alkaloids, oligopeptides and/or enzyme/protein oligomers in the role of "receptor", can therefore be altered, stimulated or inhibited with some other chemical).

Nonetheless, it is also possible that as long as the effect is detected downstream (and I'm talking via nerve cells and whatever internal processes), the end result is that the genetics involved code for a certain level of receptor presence and activity, and will always try to reestablish homeostasis here just as it does everywhere else. So likely in the end, the only "permanent" solution would likely be alteration of the gene(s) involved via first understanding the particular sequence of codons reponsible for this process, then conduct in vitro receptor studies using cells engineered with different codons reversed in, until a means of stopping the tolerance process or eliminating the gene altogether, if it can be done as an isolated artificial mutation that does not induce other changes. This is representative of the problem (now) with the intentional design of genetic codes and the replacing of natural ones with them or their elimation altogether.

One other thing, that is quite relevant here, is that there is a very strong correlation between a very low IC50 value for a ligand and receptor system, and its overall "potency" with respect to opiate effect, antagonistic effect, or activity in the role of mixed ag/antag. However I've yet to see any broad and repeated correlations between receptor response (internalization or metabolism or lysing of a particular sequence) to continuous ligand presence and the development of tolerance. Even the rate of tolerance development vis a vis various response types has yet to be firmly established, with mixed results. Clearly their is some effect, as shown most prominently in the "gestalt" effect demonstrated for methadone and morphine administered together, however, even this seems to be only a transient rate effect and is more pertinent to analgesic strength, and tolerance does still develop nontheless. Main point is that the previously mentioned (in earlier posts) model is a useful and fairly accurate one that can understood and provide information to the layperson in a useful concise way, without requiring background knowledge in chemistry, biology, biochemistry and metabolics, and I have found that many here do understand the main aspects of this when explained this way. And as far as heroin goes, I have no logical or research based reason to believe its stronger effects relative to morphine are a direct result of lipophilicity and its effects on BBB membrane penetration, after all there are a number off substances known to be unable to penetrate due to the presence of too many polarized or hydrogen bonding sites, and its also know that at the receptor upon administration of heroin, that the primary ligand present is still morphine, which is enough to convince me of this being the dominant explanation for its increased potency, as well as the knowledge that ester hydrolysis is one of the easiest linkages for the body's (and brain's) enzymatic processes to "lyse" or more appropriately, catalytically hydrolyze. This is not to say that diacetylmorphine would not be a more powerful agonist and/or have a higher IC-50 were it not hydrolyzed, only that the process is so fast and can occur directly within the brain, unlike say codeine which requires liver based metabolism to demethylate it. Anyways, this post just got way too long, as usual for me.

[SpecialGuy69]

didn't van der Waals kill that hot blonde in Aruba?

[robojunkie]

I think that's van der Slupe or something like that. His forces however appear to be a little stronger than van der Waals' forces since he has virtually admitted to being at least part of killing her or CYA'ing it. His forces would be his lawyers, whereas van der Wall's are electron promoted inductive effects, as in two non-polar molecules, say 2 hexanes, should repel, right, as the electrons are "outside" and are like charges? But no, the electrons in hexane 1 cause a change, however slight, in the electron orbital density, where the second hexane now has an induced weak dipole where the positive side is closer to the first hexane, and therefore they have a very weak attraction.

Nothing like some good chemistry to ruin a perfectly good joke, hey agent o?

http://www.ch.ic.ac.uk/rzepa/mim/environmental/gifs/24d.gifhttp://www.ch.ic.ac.uk/rzepa/mim/environmental/gifs/245t.gif
Oh, those above together, are YOU. Ie, Agent Orange. What nice people from the website I got them at, they even made that 5-chloro orange. They are called individually by the names 2,4-D and 2,4,5-T. Really they would be called 2-(2,4-diclorophenyl)-acetic acid and 2-(2,4,5-trichlorophenyl)-acetic acid. Pretty toxic, but far worse, and a side reaction in their production is the following:
http://www.ch.ic.ac.uk/rzepa/mim/environmental/gifs/dioxinr.gif
which as you can see (as I don't use my own chemdraw here), is the archetypal "dioxin" toxin, 4,5,4',5'-tetrachlorodibenzodioxane. This shit will really fuck a person up, and make 'em real low. About negative six feet low.

[stvip]

hat agonism requires "activation" (whether it be via H-bonding at a particular AA, or pi-stacking or a number of van der Waals interactions) and that in particular, this characteristic is common amongst all agonists.

But activation of what? You can't get rid of the complexity even at this basic level, if you keep in mind the recent evidence of dimerized signaling. An agonist binding and dimerizing mu-delta together can send a very different signal than mu-mu (in the thread "At the end of the tunnel" I discuss the molecule MDAN-21, which is a mu-agonist moiety bridged to a delta-antagonist moiety, and so far in studies, it exhibits high analgesic potency, complete lack of tolerance or dependence, and failure to induce place-preference, suggesting lack of euphoria).

The antagonist, and more importantly the so-called "mixed partial agonist/antagonist" is the more precise example of a ligand type that has "unusual" activity as a result of its inability to confer the necessary changes in tertiary structure to cause an action potential to be reached internally

We're still very far from action potentials (i.e: an electric signal brought upon my polarizing/depolarizing the membrane by means of opening ion gates/channels). This is still at the level of the initial signal received at the opioid receptor. Of course, once that signal is received, there are a whole lot more variables pertaining to the cell state that determines what the cell eventually does (including possibly communicating with other cells via action potentials).
At this stage, the best that we can say is that the signal is transduced by various phosphorylation events relating to the G-protein. Even this is a gross simplification, because the G-protein is itself comprised of several subunits, varies, and there are all kinds of other factors involved. Generally in GPCRs, the signal is then carried on by cAMP (and sometimes cGMP), and can involve all kinds of further events within the cell, including causing long-term changes due to activation/suppression of genes.

Yes, methadone and morphine for example, provoke very different secondary responses as a result of their "constant" presence at the receptor, but whether by internalization and presumably lysing of the peptide structure, or external inhibition via some other mechanism, the concept of tolerance still does not seem to really vary all that significantly.

Actually, to me it seems there are several redundant pathways of tolerance, possibly interfacing, possibly independent. For example, beta-arrestins are universally important in mediating GPCR tolerance, yet it seems herkinorin somehow binds to the receptor as an agonist, yet doesn't cause beta-arrestin involvement. Nevertheless, cellular changes indicative of tolerance occur. Then there's the whole issue of associative vs. non-associative tolerance, the former suggesting the involvement of even higher-level complexity systems.
The point is that biological systems often have redundancies, and thus it's extremely difficult to pinpoint that "one" enzyme or pathway that needs to be altered, because sometimes there simply isn't such.

Now as for the lipophilicity explanation of diamorphine's superior efficacy, after rereeading some of the material about it, it actually might not be a bad explanation for the "rush" sensation. You can also find plenty of research suggesting that an important distinction is having a substitution at the 6- position (so diamorphine, 6-MAM and morphine-6-glucuronide share the property of better euphoria, less side effects).

But then, you can always run into some research that calls into question some of your basic assumptions, like here:
http://jpet.aspetjournals.org/cgi/content/full/288/2/438

Anyhow - always glad to have a real chemist become interested in Biology. We need experts from other disciplines.