single and double bond at the 7,8 and the strange

[luvrofopies]

double bond at the 6,7.(ran out of title room). This thread is meant to discuss the differenced in metabolism, half life, histamine reaction, receptor and sub receptor binding and what ever else you can think of. (rescorcinal feel free to chime in);). this also only apply's to phenanthrene/morphinan opioids, no fully synthetics. so anyways I'm finally on the broad and able to share my thoughts.

from my research for a half a year and comparing all the well known and rare and forgotten opioids and the metabolism and half lives and recepter binding of them, its easy to come to the conclusion that opioids with a double bond at 7,8 tend to release more histamine than 7,8 saturated( means turned to single bond for you non chem guys). i think the double bond also tends to make the opioid more susceptible to metabolic attack and almost always reduces the half life. so lets look at our old friend morphine, great opiate and good euphoria but a half life of 2-3 hours. then lets look at dihydromorphine which is just morphine without the 7,8 double bond and it has a much longer half life of 4-7 hours and less side effects profile than morphine and it is slightly more potent. In one particular case hydromorphone with a single bond at 7,8 has a very short half life and one of these anomalies that i have yet to figure out. most other morphinones have longer half lives than morphine. whereas oxymorphone which is just 14-hydroxy-hydromorphone to my knowledge has a much longer half life of like 7-9 hours.

now we get to the weird double bond at the 6,7 position. not many opioids have them as far as i know its just thebaine, which also has a double bond at the 7,8, oripavine which also has the 7,8 double, and thebacon aka dihydrocodeinone enol acetate which is sort of an acetylated hydrocodone. you would think that would be a mistake and its actually the 7,8 but i checked many sources and they all say 6,7....strange. i think this 6,7 double bond also make thebaine and oripavine act strangely and be more of a stimulant and makes you convulse. check the structure of it, there is really no reason that is shouldn't behave like a typical mu agonist. except for maybe the methyl group on the 6 position. too bad no ones ever got to try thebacon and see for themselves. well this is sort of what i've been thinking about the past few days and im looking forward to a good discussion. i checked to see if there was a thread like this and could not find one. have at er!

[Mayo]

Among other things, you want to know why or how the position or presence of a double bond effects the speed or ability of an enzyme to convert the substrate?
The enzyme will catalyze a specific reaction, giving a specific product depending on the substrate.
Looking at the structure of the substrate, the binding pocket and the reaction being catalyzed by the enzyme,
it should be apparent why a reaction is fast/slow/possible if you know something about chemistry.

Have you been researching this for a year and a half? What are your conclusions?

[luvrofopies]

well i just got into chemistry and pharmacology and the binding of the opioid recepter like 6 months ago so no i don't really know much about chemistry but i am quite interested. i have not taken any classes except for high school chemistry which really doesn't teach you much but it is a start. when i go to collage next semester i plan on taking some chem classes. everything i learned so far is from this site and research papers on the internet. i know i don't know as much as most of you chem guys here i just wanted to get some opinions what people thought of double bonds and how they affected the things i talked about. turns out i need to take some real classes to actually be able to make a coherent and interesting thread. i just thought it might be interesting thats all. i guess my only question is that double bond at 6,7 and why they change the binding profile of thebaine and opiravine so drastically. when a double at 7,8 only really releases more histamine and has a longer duration. im not a noob about opiates but apparently i am one when it comes to chemistry.

[Mayo]

I see now you said half a year, not year and a half in your first post.

You mentioned in your first post you wanted a discussion of double bonds and difference in metabolism,
but in your writing you didn't say anything about how the presence or location of a double bond would affect the chemistry being done.
That was a telling omission. Thank you for making clearer your level of chem knowledge.

i guess my only question is that double bond at 6,7 and why they change the binding profile of thebaine and opiravine so drastically. when a double at 7,8 only really releases more histamine and has a longer duration
I can't give you an answer to that right now, I'd have to look into it first.
This does sound like a topic resorcinol would be interested in discussing tho, maybe he will answer your question.

edit: i do think the questions of if/how double bonds affect histamine release, and how they alter receptor affinity are interesting ones.
I wonder if the structure of any opi receptor binding sites been determined.
That would go a long way in determining why the presence/location of double bonds affect affinity.

[luvrofopies]

yea there arent too many threads about singles and double bonds effecting said things, but theres multitudes of substitutions and 3, ketones at 6, esters, ethers, 3,6 diesters you get what im saying. oh and another favorite topic would be the 14 substitution with anything other than a plain old hydrogen. all that other stuff has been covered. hopefully some others will chime in on there thoughts or on the single/double bond situation.

[resorcinol]

You've touched on one of my favorite topics.

I tend to agree with you that indeed, when that bond between the carbons at 7 and 8 is double, the opioid is more likely to cause histamine release. Codeine, which posesses that feature, is incredibly efficient at releasing histamine from the mast cells.

The interplay between the bond nature between 7 and 8 and the oxidation state of the sub on position 6 is also fascinating. When the double bond is present, oxidation of the 6 moiety to a ketone/carbonyl group REDUCES potency. When the double bond is absent (saturated to a single bond), potency is increased, and when the 6 moiety is oxidized to a carbonyl potency is increased even more --- the opposite of when the double bond is there. Very interesting. Normally having a methylether at 3 on the -OH greatly reduces potency. However, this is much less of an issue of that double bond is saturated at 7 to 8 and the 6 moiety oxidized to a carbonyl. This allows for active, non prodrug, opioids with a methylether at 3 (hydrocodone and oxycodone).

Now I'm not really sure why the opioids with the double bond at that position are better at releasing histamine. Maybe there's a paper out there about opioid histamine release SAR that is hiding somewhere and could be dug up.

14 substitution is also super, super important, and a serious love of mine. It's a real potency booster. The 14-hydroxy-hydrocodone (oxycodone) is widely considered superior in euphoria and potency over plain hydrocodone. Bigger subs on 14 GREATLY increase potency, with fentanyl potency and greater than fentanyl potency opioids existing. This could be an avenue to produce a very potent opioid painkiller that actually has excellent bioavailability orally (3-methylether protects from first pass attack pretty well). Very potent short acting opioids with great oral bioavailability are lacking. Oxycodone is so popular because it is currently the only one that fits that bill somewhat. However, we can go so much stronger than oxycodone by esterifying that hydroxyl at 14 --- and the oral bioavailability would likely be maintained. Hydrolysis at 14 of esters is likely slow-ish due to steric hinderance ----- non-ester big substituants there could increase metabolic attack resistence even more.

Big subs there increase potency so much because they result in compounds that more closely match the site of interaction on the mu receptor sterically. Adding a long chain with an aromatic ring at the end on 14 position in phenanthrene opioids makes them more fentanyl-ish in 3D space. There's probably a hydrophobic pocket in the mu receptor that this moiety fills, increasing affinity greatly.

[luvrofopies]

i love reading your posts/threads resorcinol, as u and others really turned me on to the whole substitution at certain positions. and the one that interests me the most right now is that awesome 14 substitution. i not only think it increases potency but also is more receptor binding friendly and the mu subtype that is responsible for euphoria. of course oxycodone is more euphoric than hydro and being that the only difference is hydroxyl at 14 one can only only conclude that the 14 has some play into the euphoric side effect of opioids. ive read many sources and most say mu2 is responsible for euphoria but a few also say mu1 so i guess were not too sure yet on where euphoria comes from. too bad not to many opioids come with the 14 sub, oxycodone, oxymorphone, hydromorphinol, and a few others "like the irreversibly binding agonist oxymorphazone" that arent too known about. then we have metopon which is not too special in itself but has some amazing 14 sub derivatives. 14phenethylmetopon, 14ethoxy, 14methoxy all are at least a few hundred to thousands times the potency of morphine. its to bad that we dont have more substitutions at 14 than we do now. and if a hydroxyl at 14 makes the drug more euphoric like hydromorphone to oxymorphone too i can only imagine the euphoria of some of these metopon derivatives. your idea on making a good potent opioid with a good oral bioavailability is another great topic and with 14 substitutions being so strong 14 cinnamyl oxycodone would be the best place to start. 14cinnamyloxymorphone has already been made so i dont think its too far fetched to see it. the 14 sub would increase the potency while the carbonyl group will still retain its good oral bioavailability. you have made great threads res, keep it up!

[luvrofopies]

i just realized that i said the carbonyl on oxycodone is responsible for good oral bioavailability but its the methoxy at position 3 is responsible for good oral bioavailability duh stupid me

[resorcinol]

You're right, in the SAR studies on oxymorphone, it was found (of the substituents tested) that the cinnamic acid ester at position 14 produced the most potent agonist. It's incredibly likely that this extrapolates well to the -codone (a methoxy group on 3) relatives. It may even be proportional (such that the potency of oxymorphone:14-cinnamyl-oxymorphone is proportional to the potency of oxycodone:14-cinnamyl-oxycodone). If that was the case, the potency could be calculated mathematically. One would have to be sure to do the proportions on IV potency of all drugs to correct for differing bioavailability by other ROAs (bioavail is 100% for all via IV administration, and therefore the ideal route to use for bioavail correction). However, I wouldn't COUNT on it being perfectly proportional as a relationship if only for the reason that these opioids will be VERY potent, and if that relationship is not perfectly proportional, ODs could result with the 14-cinnamyl-oxycodone drug (if the potency was greater than expected proportionally - if it was less potent than expected, nothing bad like OD would happen, you'd just feel it less than expected and boost the dosage).

Both the cinnamic acid esters at the 14 -OH group on oxycodone and oxymorphone would be candidates for administration by transdermal patch due to high potency. I'd like to see a phenanthrene class opioid in a transdermal patch ala fentanyl since I personally feel that phenanthrene class opioids are somehow superior for pain relief than piperidine class opioids. We've got Transdursufentanil (sufentanil transdermal system) coming out within a few years, but that's another piperidine opioid of the fentanyl subtype. Some people may not agree that phenanthrene opioids are superior overall, but I know some people feel that way. It would give more options in the transdermal arena for people who aren't jazzed by fentanyl subclass piperidine opioids.

In the case of Transdursufentanil, I think the pharma company (Durect/ENDO pharma in the U.S.) is making several more important mistakes though: 1)the matrix design doesn't work well for some people 2)7 day patch. Stupid, stupid, stupid IMO! Not only does it present a ferocious OD potential for people who try to use it buccally and miscalculate the amount needed (there's a LOT of sufentanil in a 7 day patch!), but it also presents a logistical problem. These patches aren't perfect --- sometimes they fall off early. It's already an issue with the 3 day duragesic patches (since CII drugs can't just be filled early if one runs out for a legit reason) and it will be an even bigger problem with a 7 day patch. I think the BEST type of transdermal patch is a once daily (q24 hr) patch like Emsam (selegiline transdermal system), which is an antidepressant of the irreversible MAO inhibitor type. The makers of opioid transdermal patches should follow the Emsam example and make patches meant to be changed once daily. I find that more convenient than worrying about it sticking for multiple days. With a one day patch if it falls off, it's not too long till you can change it out --- multiple day patches, if it falls off, it's a problem and a headache to deal with. It's not inconvenient to pull a patch off and stick a new one on ONCE A DAY -- it IS inconvenient to try to deal with a multi-day patch that decided to fall off (re-sticking does NOT work -- it does a LITTLE bit, but once the seal is broken once, I've found, the dose rate is drastically reduced and you'll feel mildly dopesick and in pain for CP patients). Daytrana (methylphenidate transdermal), like Emsam, has the right idea --- change it once a day. Ugh, I just don't know what Durect was thinking with a 7 day patch. It's a given that when they come out there are gonna be ODs on the news because of the insane amount of sufentanil in each patch which looks deceivingly tiny, and there's the sticking issue on top of that. WTF people?

I personally don't like transdermal patches, but for my taper I was only allowed to use duragesic b/c doc thinks temptation to abuse is reduced due to it not being in easy-to-pop pill form. To a degree doc is right, patches are more of a procedure to abuse than pills are, but doc is wrong about duragesic being "abuse proof" --- we know that. Meh. I don't think my doc thinks they're totally abuse proof or anything like that, but I think my doc does underestimate their abusability quite a bit. I'm behaving and tapering anyway (unlike during this past summer) so it's a moot point. I mostly have cravings under control. I've treated myself once in the past five months or so opioid wise.

Back to SAR and opioids:

Even if it's not a perfectly proportional relationship, the cinnamic acid ester of oxycodone at position 14 is gonna be far more potent than plain oxycodone --> it wouldn't make sense for that to be untrue from a SAR point of view. It can be said with confidence. The thought of that particular drug is enough to get any opiophile who never got into needles worked up and giddy. It's gonna have the "punch" of oral oxycodone (rapid uptake from the GI tract and excellent bioavailability due to the resistence to first pass metabolism the 3-methoxy group imparts) but be much more potent than oxycodone is. For oral opioid users, it would be a dream come true.

Another thing about 3-methoxy opioids that I can't really call "SAR" since this is totally subjective: I personally find that while 3-methoxy opioids are weaker agonists than 3-hydroxy ones, they're more euphoric and activating / speedy. That's right up my alley. It's part of the reason why I defend hydrocodone which gets a bad rap IMO (it's not THAT weak ... if you need 100 mg oxycodone HCl, a CWE of 200 - 250 mg hydrocodone bitartrate should have you pretty high! -- the issue is availability of the drug in large enough quantities I think. There is no "HydroContin" or "Hydro IR" ... only low dose Vicodin, Norco, etc with APAP. In oxycodone's case, there's "OxyContin" and "Roxicodone (Oxy IR essentially)" in addition to the lower dose versions with APAP like Percocet, Percodan, and Combunox. This personal feeling of mine about 3-methoxy phenanthrene opioids extrapolates to my feelings on oxycodone: ie -- it's my favorite opioid on the market (that's readily available). I prefer oxycodone over heroin, morphine, PT, fentanyl, and hydrocodone. Yet another reason why a nice large hydrophobic substituent at position 14 of hydrocodone excites me: I suspect it would retain that speedy / activating type buzz that I prefer while increasing potency significantly.

[luvrofopies]

14-cinnamyl-oxymorphone is rated at 114 times as potent as its parent compound, now thats quite a big fucking increase in potency. i also agree that if the potency of 14-cinnamyl-oxycodone wouldnt be 114 times as potent as regular old oxy but im sure it would give an increase of at least fentanyl potency. nice touch on on the transdermal possibilities of cinnoxy but if you have a potent drug with great oral bio i think that oral use would most likely be the number one roa. buprenorphine is made in a trasdermal patch but i dont think that its available to public yet or at least very rarely prescribed. so we would have one phenanthrene class opioids in patch form. but this is because we dont really have good strong phenanthrene opioid on the market comparable to the potency of fent.

u are absolutely right on the idea of a 7 day sufent patch is completely retarded. if they make it all the matrix design like mylan fent patch then it will be a little safer than if some were made in the gel form. it would be a great patch to abuse but very scary for people who have no clue what they are doing and pop a whole 80mg oxy just because its only ONE pill. well this is only ONE patch and the same dangers apply.

man i hate it when people talk shit about poor ol hydro. yea people have to take alot of it if they have a good tolerence but any trained monkey can do a cwe that takes 5 to 10 mins. as of right now i can still get high on 100 to 150 mgs of hydro and its a pretty good high,(but im planning a taper soon i can get back to my base tolerence of 30-40mgs of hydro.) oxycodone is also my DOC and but pretty hard to come across around these parts. i can only get percs every so often and ir or oxycontin is very rare. so my point is hydro is better than nothing and will get even a person with a decent tolerence high. might sound crazy but i enjoy the poppy seed high better than anything other than oral oxy. my usual dose would be 2 or 3 pounds and god damn that high lasted all day and was quite speedy. too bad the owner of the small place caught on and took them off the shelves.....fucking asshole. got 50 jumbo pods but didnt feel anything off them with a low tolerence, and took 10 my first time. must have been bunk pods and im ordering purples soon.

i wonder why the drug company's haven't considered these 14 substituted opioids that just seem perfect and better than what we have now.