Opioids Can anyone shed light

[StartedHydro]

on what exactly makes an opioid/opiate potent? What is the contributing factor for an opioid to have a high affinity, low affinity, dissasociation rates, relative strength? For instance what is it in regards to buprenorphine that makes it so special in the sense that it so potent in small doses? Why do certain opioids/opiates when IVed within sec's effects are pronounced and while others take minutes or hours to take effect?

What is it about these substances that cause so much variance in their unique profile? I guess im trying to understand the chemistry ofopiates/opioids. Can anyone direct me to a page that has solid information thTs not to basic or to advanced? Thanks in advance, and I really only surf this forum, hence me posting this here... if this is not appro discussion here my apologies and just direct me to the proper place for this type of discussion, thanks again.

 

[StartedHydro]

Also, since buprenorphine is a partial agonist but at the same time so potent, what happens to tolerance? Say im maintained on 1 mg of suboxone twice daily twelve hours apart. 2 mg per day of buprenorphine, and the reason I found my way on bupe was a 250-350 mg day habbit of OC80's, mostly. It was mostly oxy but it was mixed with any other opiate/opioid that was around. I could take 160 mg of methadose(liquid Mdone) and just barely notice any euphoria, so with that in mind of what my tolerance ONCE was like, with my bupernorphine at 2 mg a day what should my tolerance be now? I know that question cant be answered in a as matter of fact type reply... but with bupe being a partial agonist at the same time being so potent what happens to tolerance?

 

[sekio]

Tolerance is essentially impossible to put numbers to, you just have to know your body and the respinse it will give you from drugs. Notably, low dose buprenorphine is going to be closer to a full agonist and therefore "worse" for your tolerance because of metabolism to norbupe.

Partial agonists still develop tolerance, the classic example is THC (partial agonist at CB1) versus the JWH-series (full agonists). JWH-xxx have been found in many individuals to develop tolerance much more rapidly than THC, but regular cannabis use will still make you less sensitive to the other cannabinoids.

The major contributing factors to an opioid drug's potency:
1. Distribution through the body, if the drug is not water/fat soluble in the right way it won't diffuse through the blood-brain barrier, e.g. loperamide
2. Affinity for mu opioid receptors (Low Kd of compounds)
3. Activity at mu-OR. (For instance, naloxone binds very tightly but does not activate mu-OR). The molecule has to be shaped right to twist the opioid receptor into activating. There was a SAR study that I believe MurphyClox posted a while ago on the binding orientations of different opioids, it was neat to read.
4. (this is minor) active metabolites, i.e. codeine is transofmred to codeine-glucuronide & morphine.

Very basically, opioids are like any other G-protien receptor ligand. Essentially they are little 'keys' that fit perfectly into the receptor and cause it to change shape. Some keys fit more cleanly than others, and those are the "potent" opioids.

 

[StartedHydro]

Thank you, Sekio. By chance do you have any links for information regarding information on explaining "mu-OR,Kd of compounds"? Hoping to find solid information that is not to advanced but at the same time not to basic. Also trying to understand things such as, "Some keys fit more cleanly than others, and those are the "potent" opioids." For instance, Bupe from my understanding does not bind perfectly to its rec, but is reffered to as potent. Whats the difference between potent and strength?

Thanks once again for your time.

 

[sekio]

Here is the thread about opioid SAR.

Unless you have a working knowledge of cell biology and chemistry the mechanism of action of G-protien ligand drugs is hard to explain. I'll try the best I can though.

The mu-opioid receptor, like other receptors in your body, is a special type of protien that belongs to a family called the G protien transmembrane receptors. Protiens in your body can change shape when their environment is changed - say, presence of other compounds, or presence of acid, or heat, might cause a receptor to change shape and "activate" somehow. The receptor protiens are connected to other protiens in the cell that "notice" when the receptor changes shape - these other protiens are then activated or deactivated, depending on how the receptor shape changes, to alter the chemistry inside of the cell.

Generally, most receptors are shaped so that other certain chemicals "ligands" are just the right shape to fit into the nooks and crannies of the receptor and force certain parts of the protien apart (or together) to produce an effect. Some chemicals "stick" tighter to the receptor protien than others - this is called the binding affinity, and is ususally represented by Kd (dissociation constant). But just because a chemical sticks to the protien, doesn't mean it changes its shape - some compounds don't produce the same effect as the agonist, or less of an effect. For instance, ketamine "sticks to" the mu-opioid receptor, but doesn't cause it to activate like morphine does. In the same vein, buprenorphine sticks really tightly to opioid receptors, but activates/twists the receptor much less than morphine or fentanyl would.

 

[tricomb]

Awesome explanation, thankyou Sekio.

 

[StartedHydro]

Perfectly done, Sekio... thank you for your time.