Receptor interaction and drug circulation

[adder]

What I want to make clear, being agonist, antagonist or partial agonist doesn't determine how long the drug stays boung to the receptor. I know it has already been mentioned in a way. Partial agonism only means a drug has a lower inner activity than a full agonist. Buprenorphine stays long on the receptor because it's just a high affinity and shitty inner activity so it activates the receptor only partially.

By the way, any source with some comparison chart with affinities of opiates and synthetics (morphine, hydrocodone, hydromorphone, oxymorphone, and other worth notice derivatives)? I'd be grateful. Papers on separate drugs with numbers are welcome as well of course.

 

[Ham-milton]

Barbs lock open the chloride channels on the GABAa receptor don't they, isn't that why they are compared to benzos, which bind allosterically and do not activate the receptor directly in the abscence of GABA, a lot more dangerous?

What about depolarising neuromuscular blocking agents like suxamethonium (or it might be succinylcholine, in my current state my capacity to look it up is diminished somewhat

they're the same thing, but yeah, it is.

 

[Ham-milton]

Hey, that's the one that I presented my understanding of partial agonists on (which was contray to what MobiusDick said) and you presented what he said as evidence against what I said!
So which is it!!?!?
I'm sooo confused now.

Hey, I was just agreeing with the professor! That's what you get for trusting someone

 

[MurphyClox]

I have not seen any drug that binds and stays bound forever

But they exist. When ligand and the target are covalently linked, the drug stays forever, i.e. until the target is degraded/destroyed by metabolic procedures. Examples: Irreversibel inhibition of serine proteases by diisopropyl fluoro phosphates; irreversibel inhibition of AcCh-esterase by nerve gases (soman, sarin, tabun, VX). Of course, you will hardly find any pharmaceutical drug showing this ability because the toxicity would be far too high. In other words: Such a compound would never make it as a pharmaceutical agent...

And: It was already mentioned that occasionally the affinity of a substrate can be so high that it also stays until the receptor is degraded. Receptor proteins have a certain halflive. I guess, if this time is exceeded then the substrate can be considered as poison. So, no covalent binding in this case but just f*$%& high affinity

Murphy

 

[5-HT2]

Whether or not a drug binds and unbinds several receptors or binds a receptor and stays bound is primarily dependent on its dissociation constant or K(off). Certain drugs, such as morphine, promote receptor endocytosis, which may limit the drug's access to other activatable receptors. Partial agonism simply means that a drug does not have all the activities of a full agonist, and has nothing to do with how long it remains bound to a receptor.

 

[MattPsy]

^ The end result of a longer dissociation half-life, however, would be that of a partial agonist though, would it not? because once it's activated the receptor, the time that it's spent still bound afterward it is in effect acting as a competitive antagonist. Endocytosis could be considered the same too, because of this effect... You're right though, I don't think we need to be considering the dissociation halflife under most circumstances as most drugs dissociate very quickly and as such aren't exerting much of their effects via this mechanism...

 

[Dondante]

^^I don't think so. AFAIK, an activated receptor will continue to trigger downstream signaling events until the drug dissociates and the receptor resumes it's inactive conformation. Binding of a drug is not a 1:1 signaling event resulting in a single intracellular signal (i.e. an activated G-protein). From what I understand, there can be multiple activated G-proteins as well as activation of other independent pathways such as direct ERK signaling with the binding of a drug.

Affinity and dissociation constant wouldn't have an effect on the scale you're talking about, although I'd guess they'd influence the ED50. I'm not sure on this, but I believe downregulation and receptor internalization are due to prolonged signaling at the level of the synapse (not the level of the individual receptor).

 

[leungkachong]

Regarding drugs that 'never leave the receptor':

Mechanisms which someone might poorly describe as irrevesible, come in two varieties. One is covalent modification of the receptor (ie - acetylsalicylate and COX), resulting in an inhibition of signal.

The other, usually referred to as quasi-irreversible binding, and characterized by 'slow/tight-biding' (which means that there is a secondary conformational change with poor kinetics which can occur where the receptor clamps onto the drug so strongly that denaturing the enzyme is necessary to separate drug and binding site). This is the case for the toxic acetylcholinesterase inhibitors like methomyl and sarin, which people usually mistake for irreversible.

 

[vecktor]

Regarding drugs that 'never leave the receptor':

Mechanisms which someone might poorly describe as irrevesible, come in two varieties. One is covalent modification of the receptor (ie - acetylsalicylate and COX), resulting in an inhibition of signal.

The other, usually referred to as quasi-irreversible binding, and characterized by 'slow/tight-biding' (which means that there is a secondary conformational change with poor kinetics which can occur where the receptor clamps onto the drug so strongly that denaturing the enzyme is necessary to separate drug and binding site). This is the case for the toxic acetylcholinesterase inhibitors like methomyl and sarin, which people usually mistake for irreversible.

The modus operandi of the organophosphate cholinesterase inhibitors like sarin is to phosphorylate serine residues in the esterase, so once they interact the esterase is as good as fucked.

 

[hussness]

I have a couple of questions that go along with the original post:
If a drug has difficulty crossing the BBB into the brain does it have the same degree of difficulty crossing back out into external circulation? In other words, is the BBB more like a one-way or a two way valve?
Is it possible for a drug to cross the BBB and then get plasma bound within the brain?
In regards to "drugs that never leave the receptor" aren't the original MAOIs examples of truly irreversible binding?

Wow, my lack of background in physiology and pharmacology is really coming out here. I sound like a total noob. Great question though, Jamshyd.

 

[MurphyClox]

The other, usually referred to as quasi-irreversible binding, and characterized by 'slow/tight-biding' (which means that there is a secondary conformational change with poor kinetics which can occur where the receptor clamps onto the drug so strongly that denaturing the enzyme is necessary to separate drug and binding site). This is the case for the toxic acetylcholinesterase inhibitors like methomyl and sarin, which people usually mistake for irreversible.

I have to disagree in this case as some modifications are really permanent and therefore not just 'slow/tight-binding'. Example?! Like this one:

The modus operandi of the organophosphate cholinesterase inhibitors like sarin is to phosphorylate serine residues in the esterase, so once they interact the esterase is as good as fucked.

Without any auxiliary reagents/antidots the phosphorylation stays. Thus: Irreversibel. So, I would not only say that they are as good as fucked, no: They are fucked. Period. I agree more with Vecktors interpretation.
To underline this statement you can also look at the possible antidots: Atropine and alike are competitive to AcCh (so they compensate the lack of work that the enzyme is normally doing, i.e. cleaving AcCh into choline and AcOH). Oxims are the auxiliary antidots I mentioned. They work IFAIK by removing the phosphorylated group.

If a drug has difficulty crossing the BBB into the brain does it have the same degree of difficulty crossing back out into external circulation? In other words, is the BBB more like a one-way or a two way valve?

It should leave the brains as easy/difficult as it entered it.

In regards to "drugs that never leave the receptor" aren't the original MAOIs examples of truly irreversible binding?

I don't know about that one. Can anybody comment on this one plz?! Interesting point. MAO are no receptors but targets for xenobiotics in a broader sense and apply to this discussion as well, I would say. What compounds do you mean with the term "original MAOIs"?

Peace! Murphy

 

[vecktor]

I don't know about that one. Can anybody comment on this one plz?! Interesting point. MAO are no receptors but targets for xenobiotics in a broader sense and apply to this discussion as well, I would say. What compounds do you mean with the term "original MAOIs"?

Peace! Murphy

I think he is referreing to the hydrazine and cyclopropyl-trancypromine MAOI's which hit MAOB and I am pretty sure reacted with the active site thus were irreversible.