partial agonists.

[daddysgone]

we've all heard the term "partial agonist"- most often in relation to buprenorphine. while i understand this term to mean that a substance elicits only a partial repsonse from a particular receptor, i am curious as to exactly what is happening there that causes only a partial agonism. i know for sure that simply upping the dosage of a partial agonist will not recreate the experience of a full agonist. no amount of a partial agonist will feel like a full agonist. so what exactly is happening, on a chemical level, that accounts for only partial effects when using something like buprenorphine? any thoughts?

 

[Ham-milton]

This is useful:

The partial agonist in this example has high affinity for the receptor, so it remains bound for a long time once it reaches the binding site. As a result, when the partial agonist is present at high concentration, most of the receptors are occupied most of the time. However, because it has lower "efficacy" than the full agonist, only a fraction of the bound receptors can activate effector molecule. Therefore, the maximum response that can be produced by the partial agonist is less than 100% of the maximum response of the system.

from: http://sitemaker.umich.edu/maybaum.pharmacology.principles/partial_agonist#

edit: sorry, I guess I can't have more than one image on the same line. If a mod knows how, feel free to edit this w/ 4 each of alt-400-40-50-0-50.gif and alt2-400-0-0-50-0.gif

 

[Ham-milton]

I'm not sure what you mean about not contracting skeletal muscle. It's a partial agonist at nicotinic ACh receptors, only partially activating them. I'm not sure what you mean.

Decamethonium is a partial agonist at the nicotinic acetylcholine receptor.
Liu Y, Dilger JP.

Department of Anesthesiology, State University of New York, Stony Brook 11794-8480.

The efficacy of decamethonium as an agonist at the nicotinic acetylcholine receptor has never been determined. Here, we demonstrate how patch clamp recording during rapid perfusion of agonists to outside-out patches from BC3H-1 cells can be used to provide an unambiguous estimate of the efficacy of decamethonium. First, we obtain the decamethonium concentration-response relationship between 10 and 1,000 microM decamethonium. The maximum channel open probability is small (< 0.02) and occurs at about 100 microM. This suggests two alternative explanations: decamethonium is a poor agonist or decamethonium is an efficacious agonist but a potent channel blocker. To distinguish between these alternatives, we perfuse mixtures of decamethonium and acetylcholine to generate acetylcholine concentration-response curves in the presence of 30, 100, and 1,000 microM decamethonium. We use a model for activation and block of the acetylcholine receptor by both agonists to fit these data and determine the binding affinity, efficacy, and blocking affinity of decamethonium. We conclude that the efficacy of decamethonium is low, 0.016. Decamethonium is a true partial agonist.

PMID: 7678947 [PubMed - indexed for MEDLINE]

Perhaps what you read was a bit older? This is from 93, so it's not exactly new, either.

 

[daddysgone]

^^^^^^^^^^^^^^^

ummm... did i miss something. i didnt mention anything about skeletal anything! and we are the only 2 people who have written in this thread. who is losing their mind- you or I? im open to the fact that it may be me.

 

[negrogesic]

No, i referred to skeletal muscle; however i meant to post it in the other thread. Here is that post (i was referring to someone's comment):

Yes, that is similar to what I thought; they do occupy the receptor but only a portion of the receptors become active (therefore name, partial). But keep in mind there may be issues with this description, for example i remember reading that decamethonium does not meet this definition however is still considered a partial agonist because it does not contract skeletal muscle as well as ACh. So there may in fact be two definitions...

And yes, i had read it about a year ago in receptor pharmacology book that I have (or copy of it that is), which is probably quite old...

What i was trying to say that in comparison to ACh, decamethonium is simply not very effective and is for this reason a partial agonist.

So then is decamethonium not a true partial agonist because of its low efficacy as i suggested?

What i think the text i had read mentioned, is that this low efficacy is not because decamethonium is not able to activate the receptors, but because it blocks the nicotinic ion channel. This is why it doesnt conform to the traditional partial agonist definition, as it does activate all the receptors it occupies, but yet is still considered partial agonist. Perhaps im explaining it improperly...

 

[Ham-milton]

So then is decamethonium not a true partial agonist because of its low efficacy as i suggested?

It's efficacy is why it's a partial agonist.

A partial agonist is a drug that has lower intrinsic activity at the receptor site- lower efficacy- than the endogenous ligand, ACh in this case.

It's activity at the receptor is lower than ACh, and so it still activates the receptors, but less so. I don't know that partial agonists don't activate every receptor they bind to or if they simply activate them less. From what I've seen, it's always the latter and may sometimes be the former. Or maybe it's always a mix of both. This isn't well addressed in what I've read.

as it does activate all the receptors it occupies

But does it? I can't find anything saying that. I can find lots indicating that it has low efficacy, which is all that matters.

ummm... did i miss something.

Yeah, a misplaced then deleted post. So neither of us are losing our minds.

 

[daddysgone]

It's efficacy is why it's a partial agonist.
I don't know that partial agonists don't activate every receptor they bind to or if they simply activate them less. From what I've seen, it's always the latter and may sometimes be the former. Or maybe it's always a mix of both. This isn't well addressed in what I've read.

this issue is at least part of what im trying to get to the bottom of regarding partial agonists. however, in the model which you posted to illustrate partial agonist action, it seemed to suggest that while most (if not all) of the receptors are being bound to, only a small portion were actually activated. this goes against what you just said-namely that from what youve seen its always the case that they activate the receptors less, and perhaps sometimes they dont activate each receptor which they bind to.

 

[The Monkey Mantra]

I don't know how they could activate it "less". Like, for the example of an opiate, either the gamma-beta complex (correct me if I got my letters wrong) uncouples from the receptor and inhibits adenylate cyclase or it doesn't. I don't see how it could "kind of" uncouple. Maybe some agonists might be better able to keep it from re-coupling?

 

[MattPsy]

Reposting my latest comment from 'Receptor interaction and drug circulation' thread as it fits better here:

The understanding I have NOW is that partial agonists are ones that may bind to the receptor but not activate it sometimes - so sometimes they're an agonist, and other times an antagonist... leading to a kind of half-way activity when you have thousands of these drug molecules binding to their own receptors. Their efficacy (intrinsic activity) is thus the PROBABILLITY that receptor activition occurs on binding, compared to the endogenous agonist.
This same effect may also occur with agonists that have longer dissociation halflives than usual, I think, from what I can see, because they should amount to the same expression of activity... because if an agonist stays bound, the ion channels it is coupled to won't close... which means you won't get any additional action potentials generated as there should be no voltage gradient between the extracellular and intracellular space of the neuron if the channel is stuck open?

 

[Black]

I don't know how they could activate it "less".

i don't know that counts as partial agonism but there are 5-HT2A ligands that elicit less intracellular response from binding at the 5-HT2A receptor than psychedelics. i've found the following:

While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

 

[Riemann Zeta]

That definitely counts. In this case, while lisuride and LSD are both partial agonists at the 5-HT2A receptor (their efficacy is lower than 5-HT itself), lisuride has such a low efficacy in activating downstream cellular cascades, that for all intents and purposes, it is a functional antagonist. That is, it sticks to the receptor, occupying it and preventing other ligands from binding, but it doesn't do much while there.

 

[MattPsy]

It's possible for both to be partial agonists but for one to cause a particular and distinct conformation that leads to different signalling behaviours, downstream effects etc.
It's also quite possible (even likely) that not all types of receptor will have different 'active' conformations which produce different signalling.

 

[The Monkey Mantra]

So the "lesser" activation could be one of two things: Either a probability (like, it either turns it on or it doesn't, but there's only a 1/3 chance it'll turn it on) or an actual difference in the protein conformation resulting from one agonist or another that changes how well, for example, an ionotropic receptor is able to open the channel, huh? Is this how inverse agonists work? By really flipping around the protein conformation?

MattPsy, you're really helpful and knowledgeable. Thanks a ton, dude! I really appreciate your posts.

 

[Dondante]

I don't know how they could activate it "less".

My understanding is that GPCRs are not simple on/off switches. When a ligand binds, the receptor adjusts its conformation. Adopted conformations probably vary somewhat depending on the ligand, and even miniscule changes affect the degree of activity.

Additionally, a receptor in an "active" conformation will continue to activate G-proteins as long as the ligand is bound. There could be some conformations that are more "on" than others, by that I mean they could facilitate a higher rate of G-protein turnover (not sure about this though). Going from G-protein activation to triggering action potentials is a big jump though, and it makes sense that constant activation would prevent new potentials by keeping the synaptic end-plate relatively depolarized.

By that logic, wouldn't it possible that a partial agonist could be a molecule that favors a less-active receptor conformation and a lower rate of G-protein turnover, instead of a molecule that sometimes activates and sometimes does not? That makes more sense intuitively to me at least. It's also important to remember that some receptors have a certain level of constitutive activity, which allows for the classification of some drugs as inverse agonists.

The idea of degree of activation might be harder to explain for ionotropic receptors, or possibly it's all just much more complicated that the explanation I made above. I remember reading that the difference between barbiturates and benzodiazepines is that the former increases duration of GABA-mediated channel opening, and the latter increases the frequency. Multiple binding sites add a whole new level of complexity for agonist efficacy ...

I had one more question. Would it be fair to classify some drugs as super-agonists if the intrinsic efficacy higher than that of the native ligand?

I hope that post is understandable ... don't have time to fully think this out ATM.

Edit: I just read on wikipedia that psychostimulants are inverse agonists to dopamine receptors. That doesn't sound right.

 

[vecktor]

By that logic, wouldn't it possible that a partial agonist could be a molecule that favors a less-active receptor conformation and a lower rate of G-protein turnover, instead of a molecule that sometimes activates and sometimes does not? That makes more sense intuitively to me at least. It's also important to remember that some receptors have a certain level of constitutive activity, which allows for the classification of some drugs as inverse agonists.

a lot of inverse agonists bind to the inactive conformation of the receptor, thereby reducing the overall level of receptor activity. there are other machanisms for inverse agonism but this is one of the most important.

Edit: I just read on wikipedia that psychostimulants are inverse agonists to dopamine receptors. That doesn't sound right.

they could be, given that a some dopamine receptors are act as auto receptors and reduce dopamine release.

most psychostimulants are I suppose broadly categorised as indirect dopamine agonists, by acting as releasers or reuptake inhibitors and possibly also as competitive MAOI's they increase extracellular dopamine and therefore dopaminergic agonism without necesarily being DA agonists themselves.

 

[MattPsy]

Partial agonist review

Ok, i've done some more reading, and can now post a summary/review:

Introduction
A partial agonist's mechanism for it's reduction in efficacy compared to the endogenous agonist is it's abillity to act as a competitive antagonist in addition to it's abillity to act as an agonist at a receptor, resulting in a mixed activity profile. In a outcome-oriented way, this appears that the ligand in question appears only x % as effacious at producing receptor activation as the endogenous agonist at full receptor saturation by the ligand - being either "activated" or "not-activated" - although there are caveats to this that are discussed later in this review in the section on functional selectivity.
This ratio of agonist:antagonist behaviour can thus be understood as a sort of probabillity.

The reduced efficacy confusion syndrome
Many times, some have become confused with the concept of a partial agonist, considering it to be a ligand that produces a "halfway response" or such, at the receptor level. In reality, this view is actually somewhat incompatiable with the molecular basis of neurotransmission. A g-protein may either be released, or not released. It cannot be half-released. A ion channel either opens or it does not. (there are exceptions on the ion channels, but we'll ignore these slight oddities here as they really are oddities - we're trying to account for typical behaviours here, not account for *everything*...)

A model of partial agonist transmission...
A simpler and more logical explanation of receptor behaviour than the "halfway activated" model that still accounts for the same outcome exists - let us consider that a synapse contains 1000 receptors, for a simple model to give examples on.
If a partial agonist ligand has 50% efficacy and very high affinity, when a high enough concentration of it is introduced to the synapse in question, all the receptors will be bind said ligand - but only 50% will activate - in this case, being 500. This results in a diminished neuron response than if a full agonist had been used, because the elicited action potential that will result will be only half as powerful than if all of the receptors had been activated and opened their coupled ion channels... through g-proteins or not. It doesn't matter whether they are ionotropic and metabotropic receptors here.
So see, you still get the diminished response, but at a higher level (synaptic level) than at the receptor level.

Functional selectivity
However, agonists (and partial agonists too) may produce a phenomenon named functional selectivity (or ligand-directed signaling) where a ligand may evoke different signalling from a receptor, most probably by causing a different receptor protein conformation. This may have some quite interesting outcomes, as quite different behaviours (and not just those mediated by action potential generation!) in the parent neuron may occur as a result of this different G-protein activation and event cascade, with downstream effects such as receptor phosphorylation, genetic transcription expression changes, etc.

An example of this type of behaviour can be seen in the distinct signalling differents seen in hallucinogenic & non-hallucinogenic 5-HT2A ligands - user Black has helpfully provided this quote from ref 3:

While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src.

The reason that this additional type of signalling behaviour has been mentioned in this review is that it is yet another mechanism for production of different signalling behaviours, that may appear to be partial agonist-like in come contexts.


References:

Mechanistic explanation for the unique pharmacologic properties of receptor partial agonists. (Biomed. & Pharmacother. 2005 Apr;59(3):76-89)

Ligand-directed signaling: 50 ways to find a lover. (Mol Pharmacol. 2007 Nov;72(5):1359-1368 )

Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior. (Neuron 2007 Feb;53(3);439-452)

Also, thanks Monkey Mantra, i'm glad you're finding them useful.
I hope everyone finds this post useful too !

 

[negrogesic]

Ok, that clears it up then, so in most cases the partial agonists affinity is high but only a portion of the receptors occupied are activated, right (functional selectivity aside )? So my old textbook is not incorrect?

 

[MattPsy]

Correct , just keep in mind the points on functional selectivity though because the implication of it is that drug action at the receptor is not as simple as agonist/partial agonist/antagonist/inverse agonist. Activation of differential pathways in some ways could be considered to be "partial" activation I suppose, because one pathway may produce a greater neuronal response, which is why it muddies this otherwise clear explanation.

A ligand can be a agonist for one signalling pathway and an antagonist for another simultaneously, or an agonist at one and a partial agonist for the other, or even more extreme combinations potentially... and these combinations are produced by binding to a single receptor at a time!
The plot thickens, essentially, haha.

I'm thinking these differences in signalling are responsible for a *lot* of the different *feel* we experience off different drugs in the same class (ie opioid vs opioid), why some are horribly addictive yet produce less euphoria than a similar drug that is less addictive, etc. I'm hungry for more information haha, been reading all afternoon on this stuff as it is now!

edit: Added smiley face. Not sure why, it needed it, heheh. Looks far friendlier now!

 

[negrogesic]

Right, like i think the text book had mentioned, decamethonium is considered a partial agonist not because it fails to active the receptors to which it binds, but because of the efficacy loss associated with it blocking the nicotinic ion channel. So like you said, sometimes there are multiple mechanisms which complicates the matter...

 

[Black]

excellent writeup mattpsy!
i suspect activation of unbound G protein by an already actived receptor (from which the G protein did already dissociate) would also play an important role with parial agonists / general drug action, but if we want to include every detail we'd have to fill (at least) a whole book on that subject