The opioid pharmacology thread

[ampakine]

What Opioids Are
The term opiate is the word given to compounds isolated from the opium poppy. For example morphine, codeine and thebaine are all opiates. Heroin on the other hand is not present in the opium poppy so it is not an opiate. The correct term for opiate derivatives like heroin is semi synthetic opioid. There also exist fully synthetic opioids such as methadone and fentanyl which are not derived from any naturally occuring opiates. An opioid is any compound that fits into opioid receptors. There are 3 types of opioid receptors: μ (mu), δ (delta) and κ (kappa). Drugs like morphine, heroin and methadone are all opioids because they bind to opioid receptors. More specifically drugs like morphine bind to μ and δ opioid receptors. Surprisingly, salvinorin A (the active constituent of salvia divinorum) is also an opioid but it binds almost exclusively to κ opioid receptors. Often a slight change in structure can make a compound have a higher affinity for a particular type of opioid receptor. For example herkinorin, an analogue of salvinorin A has a much higher affinity for μ receptors and far lower affinity for κ receptors than salvinorin A. The result is that herkinorin has properties closer to that of morphine but also has some of the psychedelic properties characteristic of salvinorin A.

Salvinorin A

Herkinorin

as you can see, the only difference is herkinorin has an extra phenyl group attached to the acetyl group at the left hand side of the molecule. There are 3 families of opioids produced in the body: the endorphins, enkephalins and dynorphins. The word endorphin is the shortened word for "endogenous morphines" and bind primarily to μ opioid receptors.

Structure Activity Relationships.
Structure activity relationship (SAR) as the name suggests, is the relationships between the structure of the compound and its pharmacological properties. As you will see in the rest of this thread, a small change in the structure of a compound can result in a For now I'm going to use morphine as the reference compound and focus on the 3 and 6 position of morphine and its analogues.
First heres morphine:

as you can see it as -OH groups attached to the 3 and 6 positions. Attach a methyl group at the 3 position and you have codeine.
Codeine

Codeine isn't even active by itself, it must be converted into morphine by the liver but lets say it has a potency 10x less than morphine.

Attach a methyl group at the 6 position instead and you get heterocodeine:
Heterocodeine

According to wikipedia heterocodeine is 6 times more potent than morphine so that would make it 60 times more potent than codeine. Interesting

Now lets replace the methyl group with an acetyl group.
3-MAM

6-MAM

6-MAM is known to be more potent than heroin while 3-MAM is less potent than morphine. Similar to attaching methyl groups, attaching an acetyl group to the 6 position increases potency while attaching one to the 3 position lowers potency. This is why heroin having acetyl groups attached at both positions:
Heroin

is less potent than 6-MAM but more potent than morphine. This trend occurs with all sorts of substituents for example lets examine 2 of morphines major metabolites, M3G and M6G.

Morphine-3-Glucuronide

Morphine-6-Glucuronide

M3G is far less active than morphine while M6G is far more active than morphine.

Now lets see what carbonyl groups do. Oxidise the -OH at the 6 position of morphine and you get morphinone:
Morphinone

which is far weaker than morphine. Thats morphine-6-one, I can't find any info on morphine-3-one unfortunately. Can't find anything on morphine with both -OH groups oxidised either.

While codeine is methylmorphine, heres ethylmorphine:
Ethylmorphine

Ethylmorphines less potent than morphine but more potent than codeine. Thats 3-ethylmorphine, heres 6-ethymorphine:

6-ethylmorphine

Can't find any info on it though. Petty cuz I'm interested to see if it is more potent than heterocodeine or not.


Now lets examine what happens when we remove the double bond in the lower ring of morphines phenanthrene backbone. A hydrogenation of morphine yields dihydromorphine:
Dihydromorphine

Dihydromorphine is slightly more potent than morphine and a longer half-life. Morphine has a half-life of 2-3 hours whereas dihydromorphine has a half-life of 4 hours.

Similarly a hydrogenation of codeine yields dihydrocodeine:
Dihydrocodeine

Dihydrocodeine is approximately 1.5 greater in potency than codeine and has a half-life of 4 hours which is significantly longer than codeines half-life of 2.5-3 hours.

More interestingly is what happens when codeinone and morphinone undergo this reaction. The products of the hydrogenation of morphinone and codeinone are hydromorphone and hydrocodone respectively.
Hydromorphone

Hydrocodone

The potency of hydromorphone is exponentially greater than that of morphinone. Likewise the potency of hydrocodone is exponentially greater than that of codeinone. Hydromorphone is approximately 10 times the potency of morphine and 7 times the potency of dihydromorphine. Likewise hydrocodone has approximately 10 times the potency of codeine and 7 times the potency of dihydrocodeine.


Novel Opioids
The opioids discussed so far are all morphinans meaning they are derivatives of the compound morphinan:
Morphinan

Morphinans are not the only compounds that bind to opioid receptors. Many non morphinan opioids have been discovered, some of which are thousands of times more potent than morphine. A well known example of a super potent, non morphinan opioid is fentanyl:
Fentanyl

which has a potency of approximately 2,000x that of morphine. Another novel super potent, non morphinan opioid is bromadol:
Bromadol

which has a potency of approximately 10,000x that of morphine. Bromadol is an analog of the weak opioid tramadol.

 

[Alcyone]

Good idea, if it's done properly.

I believe the term you're looking for is (quantitative) structure-activity relationship (SAR/QSAR).

Edit: I think you mean adding a methyl to the 6-OH in the paragraph you just added at the end. There's already a methoxy in the 3 position of codeine.

And could you please edit glucoronide to glucuronide? The term glucuronide is derived from a class of carbohydrates called uronic acids. Common mistake, though.

 

[ampakine]

I believe the term you're looking for is (quantitative) structure-activity relationship (SAR/QSAR).

Ah yeah thats the one, thanks.

 

[specialspack]

i like this thread - I'm sure it's obvious to our more learned posters here, but I'm finding it educational.

 

[negrogesic]

Im confused as to the aim of this thread..........this topic can go on endlessly, particularly if you include the semi-synth and synthetics that can and do" break the rules" so to speak (tert nitrogen etc etc). Are we limited to phenanthrene's here, because otherwise.......the topic can go far beyond a" basic tutorial" (even limited to phenanthrene SARs, the topic can not be summarized in short). The very basic rules to naturally occuring phenanthrene MOR activities could be summarized, but such literature is prevalent.

In otherwords, as noble in intent, I see no useful "opioid pharm/SAR FAQ" for most audience. Does it take a university educated O-chem student to make good use of acetic anhydride; no. If you were to ask such cooks about the mechanisms, good luck. Some things can't (and shouldn't) be dumbed down, such as the crude meth 'cold cook' recipes prevalent online.

I know only what ive learned as an autodidact outside of med school (which isn't much), but if you have a question feel to ask. Others here are walking encyclopedias of o-chem know how, in all honestly I am far better trained at their administratipn rather than the countless SAR implications....

 

[ampakine]

Im confused as to the aim of this thread..........this topic can go on endlessly, particularly if you include the semi-synth and synthetics that can and do" break the rules" so to speak (tert nitrogen etc etc). Are we limited to phenanthrene's here, because otherwise.......the topic can go far beyond a" basic tutorial" (even limited to phenanthrene SARs, the topic can not be summarized in short). The very basic rules to naturally occuring phenanthrene MOR activities could be summarized, but such literature is prevalent.

The aim of the thread is to provide basic knowledge of opioid pharmacology for people who don't know this yet. I'd say thats enough SARs for morphinans but I might cover some fentanyl analogues because in my opinion its interesting shit and I find its a lot easier to learn when the info is compiled into 1 place and geared towards the kinda stuff you're interested in.

In otherwords, as noble in intent, I see no useful "opioid pharm/SAR FAQ" for most audience. Does it take a university educated O-chem student to make good use of acetic anhydride; no. If you were to ask such cooks about the mechanisms, good luck. Some things can't (and shouldn't) be dumbed down, such as the crude meth 'cold cook' recipes prevalent online.

I have to disagree with you there. I find it more interesting reading an explanation of concepts when they are geared towards the things that I'm interested in. For example there are hundreds of organic chemistry textbooks in which you can find everything you'd need to know to acetylate morphine but I find it more interesting to read an explanation which was written specifically for the acetylation of morphine. Thats just an example, the acetylation of morphine isn't very interesting. I agree with you about meth recipes though. Most of what you find online literally are recipes, they don't provide any info on the actual chemistry involved. Petty because its interesting shit and could help people who are fascinated with psychoactives to learn organic chemistry because you learn far better when you're interested in what your learning. Organic chemistry is interesting but it can get pretty boring when you can't see how you can actually apply the knowledge. For example I would have never learned the mechanism of a Sandmeyer reaction off by heart if it wasn't the mechanism for the conversion of GABA into GHB. Then again azo coupling reactions are pretty cool so that was a bad example.

I know only what ive learned as an autodidact outside of med school (which isn't much), but if you have a question feel to ask. Others here are walking encyclopedias of o-chem know how, in all honestly I am far better trained at their administratipn rather than the countless SAR implications....

Same here. The only reason I go to college is for the degree. That and the practical experience I gain in the labs.

 

[negrogesic]

The funny thing is, I taught 2 sessions of undergraduate o-chem lecture and labs at a rather prestigious public university (each session comprising of 2 sections, ~90 students combined). Needless to say my exams were multiple choice (and yes, im the A-E asshole); it was the 1 unit labs that were a bitch (ummm, professor, I just spilled the nitric acid....etc).

The thing is, I do not have and a graduate or PhD in chemistry of any nature (associate professors much have a doctoral degree to teach the class). I had just passed my boards; a doctor in medicine, not a PhD in some form of chemistry etc). I signed up to teach these classes in a failed attempt to reduce my residence hours; it did not work. The good thing about teaching ; its a great tool to learn (admittedly I had questions on my exams that I myself would have difficulty answering in the allotted time).

My point being.....I am not sure how something of ths nature can be summarized in an FAQ etc, and even if it was, it would require at least a basic but fundamental understanding of the more seemingly "mundane" basis of general and organic chem. If you can do it, you are a better instructor than I.....

The tricky part would be not crossing over into synthesis (which is ultimately, the bottom line; unless one enjoys jerking off to exotic chemical structures). Despite how all this may sound, I am not trying to pejorative.....

 

[altarazims]

/

One might assume that this is a definite trend but it doesn't seem to be that simple. For example remember what happens to potency when you attach a methyl group at each position, one might be inclined to think attaching a methyl group to both positions would result in a compound with a potency in between codeine and heterocodeine. Thats not the case though, attach methyl groups at both positions and you get thebaine:
Thebaine

which seems to have little or no affinity for mu opioid receptors. Anyone got any theories as to why adding an methyl group at the 3 position of codeine doesn't increase its activity? Maybe different substituents have varying abilities to activate the compound by bonding to the 6 position and deactivate it by bonding to the 3 position. Maybe a methyl group can deactivate a lot better than it can activate. That would explain why codeine is inactive by itself.

Aren't there two double bonds in thebaine instead of one? Wouldn't dimethyl-morphine/6-methylcodeine be a different compound than thebaine? I'm no chemistry person though, so I could be way off....

 

[ampakine]

My point being.....I am not sure how something of ths nature can be summarized in an FAQ etc, and even if it was, it would require at least a basic but fundamental understanding of the more seemingly "mundane" basis of general and organic chem. If you can do it, you are a better instructor than I.....

The tricky part would be not crossing over into synthesis (which is ultimately, the bottom line; unless one enjoys jerking off to exotic chemical structures). Despite how all this may sound, I am not trying to pejorative.....

Good point. You'd need some level of organic chemistry knowledge just to understand what the hell I'm talking about in this thread. I didn't think of that. Years ago when I would come onto forums like this and read pharmacology/chemistry related threads I couldn't understand a word of them. Theres no real way around attaining a basic understanding of general chemistry and organic chemistry when it comes to things like this. If I didn't already have basic chemistry knowledge starting to learn pharmacology would have been a thousand times harder i.e. grasping what things like ion channels, receptors and ligands would be near impossible without already knowing a bit about ions and molecular structures. Not to mention having some knowledge of biology and biochemistry to understand things like cell membranes and metabolism. I admit knowing how this knowledge can be applied to synthesis is a significant part of my motivation for making this thread.

/

Aren't there two double bonds in thebaine instead of one? Wouldn't dimethyl-morphine/6-methylcodeine be a different compound than thebaine? I'm no chemistry person though, so I could be way off....

Oh yeah there are. Thanks. I'm learning half this stuff as I go.

 

[negrogesic]

I think a primer on opioid MCB would be far more approachable for most.

If you want to know the most efficient route to codeinone......

 

[23536]

Thats not the case though, attach methyl groups at both positions and you get thebaine:
Thebaine

which seems to have little or no affinity for mu opioid receptors. Anyone got any theories as to why adding an methyl group at the 3 position of codeine doesn't increase its activity?

As altarazims points out, thebaine has an extra degree of unsaturation on that ring. If you have a molecular model kit, build morphine and thebaine and compare them and you'll notice that morphine has a lot more flexibility and can wiggle into a wider variety of spaces.

Also, note that thebaine's metabolite oripavine:

is analgesically active but also toxic.

Lastly, what about the structure you actually had in mind here: codeine methyl ether?

 

[indelibleface]

As a side note, more tutorial/learning threads like this might be a cool idea for ADD in the future? It might be fun to officially put out these once in a while, to be more inclusive here and make more Bluelighters more "advanced" over time.

Just a random idea.

 

[ampakine]

Lastly, what about the structure you actually had in mind here: codeine methyl ether?

I can't find any info on it. I removed the bit about thebaine but I really wanna know about the active properties of 6-methylcodeine to see if it fits the same trend as diacetyl and the mono acetyl morphines.

As a side note, more tutorial/learning threads like this might be a cool idea for ADD in the future? It might be fun to officially put out these once in a while, to be more inclusive here and make more Bluelighters more "advanced" over time.

Yeah I agree. They can also serve as preliminary tutorials for people who wanna be able to understand the kinda things talked about in ADD. We should have a system where everyone can contribute their knowledge rather than one person making the thread though. That way these threads will turn into highly educational sources of info.

I threw in a quick introduction to opioid pharmacodynamics at the top. I have loads more to add to that when I have the time. I need to do some revising on all this, I can't what exactly delta receptors are all about. I remember reading about buprenorphines mechanism of action and that it has a higher affinity for delta receptors than it does mu receptors or something like that. Gonna do some research to learn a bit about the relationship between these 2 receptors because its interesting shit.

 

[Unbreakable]

7-PET is a potent analgesic drug, 300 times the potency of morphine by weight.[1] It is related to the more well-known oripavine derivative opioid etorphin.....

Bromadol is a potent narcotic analgesic with a distinctive chemical structure. Considered 10,000 times the strength of morphine, it was first reported by The Upjohn Company in 1979. BDPC is an arylcyclohexylamine derivative also bearing some chemical similarity to tramadol and venlafaxine.

 

[Nagelfar]

Bromadol is a potent narcotic analgesic with a distinctive chemical structure. Considered 10,000 times the strength of morphine

Acetorphine is a morphinan that is near ten thousand times the potency of morphine, so that means, if I'm not mistaken, that it is also a ligand for the mu-subtype 3 opioid receptor that morphine is, whereas open chain opioids are not a ligand for this subtype; which has been shown to increase the discrimination ratio of use (again, if I'm not mistaken)

 

[Nagelfar]

Also, about heterocodeine, would anyone know if the 6-methyl group is as lipid soluble as the 6-acetyl group? Meaning would it have as quick of BBB penetration as heroin? I assume it is so much more potent because how non-liable the methyl group is to the metabolization of the chemical, so that would tie its potency to its duration, or does it bind to the receptor as a better ligand? Yet none of this usually has to do with rapid onset; which is associated with euphoria and rush sensation.

 

[Nagelfar]

Now, is Salvinorin A the most centrally active chemical substance known, or the most centrally active naturally occurring substance known? Because I know I've read its one or the other. Herkinorin being a greater mu-agonist made out of it though is a highly interesting prospect and I don't think there's an opioid addict in the know who wouldn't want to try it. Esp. since it apparently down-regulates, like certain opioid peptides, tolerance to mu-agonism at the same time.