Questions Regarding Partial Agonists

[daddysgone]

Ill admit- Partial Agonists confuse me. There is one specific issue that I wonder about, and i imagine some people here can help clear things up.

When looking at an agonist (for the sake of argument, lets consider an opioid agonist), is it a black and white issue, or is the model more like a spectrum? Let me try and explain this a bit better. Fentanyl is a full agonist, and buprenorphine is a partial agonist. However, are there substances that are more of a full agonist then buprenorphine, but not as full as fentanyl? Is there some dividing line that defines something as either partial of full? I hope I am making myself clear.
Im just wondering if in the world of agonists, there is a sort of spectrum. On one side you have partial agonists which, while they bind to receptors, they only very minimally activate them. Then on the other far side of the spectrum, you have full agonists, which bind to these receptors, and also activate them fully. Are there substances that fall over all the various parts of this spectrum? If this is the case, then you could have something considered a partial agonist that is very close to the dividing line that separates partial and full agonists. You could then have something thats considered a full agonist, but it is JUST on the other side of this dividing line. Thus, you would have 2 substances, one considered a partial agonist, one considered a full agonist, but in reality they would have almost identical agonist effects. Does this make sense to anyone? And more importantly, is this the way agonists and partial agonists work, or is my model totally wrong? thanks-DG

 

[tryp2fun]

A full agonist is a ligand that causes the full response (100 percent) upon receptor binding. Usually the natural ligand is the one that is used to measure the full response. A partial agonist is a ligand that give only a partial response (less than 100 percent) on receptor binding.

 

[daddysgone]

A full agonist is a ligand that causes the full response (100 percent) upon receptor binding. Usually the natural ligand is the one that is used to measure the full response. A partial agonist is a ligand that give only a partial response (less than 100 percent) on receptor binding.

Yes. Of course Im aware that a full agonist elicits a full response and a partial agonist elicits a partial one. However, if you re-read the questions posed in my post, i think you will see that im trying to get more in depth here, and gain a full understanding of the intricate differences between full and partial agonists. Again, specifically, im hoping to find out whether there are varying "degrees" of both partial and full agonists. Are certain partial agonists more or less "partial" then others? if you have a good understanding of these concepts and wouldnt mind re-reading my original post, i think you will see the specific questions im looking to be answered. thanks- DG

 

[shibireru]

What you're saying, that there's a continuum of efficacy at any point on which an agonist can reside, is a notion which is easy to conceive of, but which sort of falls apart when you narrow your scope of examination and look at the minutia of the earliest stages of signal transduction. G protein-coupled receptor proteins derive their catalytic capacity (their capacity to catalyze the transposition of guanosine diphosphate with guanosine triphosphate on the alpha domain of a heterotrimeric g protein) from amino acid residues; the receptor proteins are only catalytically active when these amino acids residues are exposed and in proper orientation with respect to one another and this exposure and reorientation occurs as a result of some conformational change or another in the receptor protein induced by agonism by some ligand (depending on the agonist, you may get a different conformational change). Well, since there's a fairly limited number of amino acids residues that contribute to the catalytic action of the receptor, and a limited number of functional orientations, one must expect a fairly coarse granularity in the range of the catalytic capacities/efficiencies that receptor can express.

For sake of simplicity of expression and ease of understanding, let's abandon pendantry and say that there are 11 different catalytic states that the mu-opioid receptor can occupy and that the catalytic potentials of these different states increase linearly. So:

State 0 0% of maximal catalytic capacity
State 1 10% of maximal catalytic capacity
...
...
...
State 9 90% of maximal catalytic capacity
State 10 100% of maximal catalytic capacity

Obviously in real life matters aren't likely to be so straight-forward and neat as this, but I think it gets the point across.


On the other hand, because ligands have different binding affinities for receptors, a receptor can in practice have a pharmacophore each of whose members is more efficacious than the last by a narrower margin than the total number of possible catalytic states that the receptor can assume would suggest.

**Warning**
This is just an educated guess on my part. I didn't actually read this anywhere. So take it with a mountain of salt.

 

[Hammilton]

There are lots of ligands that don't have 100% efficacy compared to the natural ligand. Then there are those that have more than 100%. It is my understanding that this is somewhat irrelevant.

Dissociation rate is a bigger issue. A drug that binds, exerts it's action but then takes a while to dissociate will be a partial agonist regardless of efficacy. LSD is a partial agonist at 5HT2a... I thought that LSD had high intrinsic activity (efficacy) at 2a, but I can't find a source for this right now. Perhaps someone else can answer this.

Hmm.. Now I'm not sure. Efficacy is obviously related. Now: how is dissociation rate related?

 

[daddysgone]

There are lots of ligands that don't have 100% efficacy compared to the natural ligand. Then there are those that have more than 100%. It is my understanding that this is somewhat irrelevant.

Dissociation rate is a bigger issue. A drug that binds, exerts it's action but then takes a while to dissociate will be a partial agonist regardless of efficacy. LSD is a partial agonist at 5HT2a... I thought that LSD had high intrinsic activity (efficacy) at 2a, but I can't find a source for this right now. Perhaps someone else can answer this.

Hmm.. Now I'm not sure. Efficacy is obviously related. Now: how is dissociation rate related?

Ok- that is an interesting point, and it certainly is involved in gaining a full (or at least more complete) understanding of full vs. partial agonists. However, I still feel that my question has not really been answered.

Well lets look at it this way. Is there an actual numerical percentage of efficacy which defines an agonist as either full or partial? An ever simpler question, does a substance truly need to have 100% efficacy in terms of agonism, to be labeled a "full agonist" If this is the case, only those substances which truly have 100% efficacy are considered full, and anything which has less efficacy would be "partial". And if this is the case, I would then imagine that there are varying degrees of partial agonists; on one end would be agonists that have so little agonism that they are closer in function to antagonists. On the other end would be substances which have near complete agonism and thus, function almost identically to full agonists.

Perhaps I am coming at this issue from entirely the wrong angle. However I tend to think of things in almost a robotic level of logic. It therefore seems to me that there is no getting around the idea that agonists must exist along some sort of spectrum, with near antagonistic function at one end, and 100% agonism at the other. My question remains however, Are there agonists which fall all up and down the length of this spectrum, such that there are some partial agonists with nearly zero efficacy, and then other partial agonists with such a high level of efficacy that they function in nearly the same manner as a true, full agonist?

I guess thats it. Id be thankful if anyone can clear this up for me, or if my way of thinking about this issue is totally wrong-headed, for someone to help me view it in the correct light. thanks-DG

 

[Hammilton]

Are there agonists which fall all up and down the length of this spectrum, such that there are some partial agonists with nearly zero efficacy, and then other partial agonists with such a high level of efficacy that they function in nearly the same manner as a true, full agonist?

No, zero efficacy makes it an antagonist --> binds but doesn't engender the right conformation

IIRC, LSD is effectively an agonist.

The major difference with the partial agonists vs. pure agonists when efficacy is high is that the partial agonists will function as an antagonist in the presence of the full agonist. Well, that's not the major difference, but for LSD, it's an important thing to know. Using a full agonist with LSD should theoretically result in a primarily LSD-like experience, the full agonist shouldn't exert a major effect.

 

[Enkidu]

Dissociation rate is a bigger issue. A drug that binds, exerts it's action but then takes a while to dissociate will be a partial agonist regardless of efficacy.

I don't think that this is true. Someone debunked that statement when I was asking Qs about I-forget-whose essay that's here on bluelight.

 

[tryp2fun]

Are there agonists which fall all up and down the length of this spectrum, such that there are some partial agonists with nearly zero efficacy, and then other partial agonists with such a high level of efficacy that they function in nearly the same manner as a true, full agonist?

The short answer is yes, the range of agonism is anything from 0 (antagonist) to 100% (full agonist). Partial agonists can have any value of efficacy greater than 0 and less than 100. A partial agonist is also a partial antagonist. It probably has to do with the ability of the ligand to shift the conformation of the receptor from the inactive to active state. Full agonists shift the equilibrium completely toward the active state, partial agonists shift only partly, and antagonists bind to and stabilize the inactive state.

 

[Hammilton]

I don't think that this is true. Someone debunked that statement when I was asking Qs about I-forget-whose essay that's here on bluelight.

Yeah, I remember that now. That essay is almost certain where I got this idea from! In fact, I think I was one of those saying it wasn't true, because there were full agonists with longer dissociation half lives.

My memory really fails me if I can't even keep straight what I believe and don't believe about an issue.

If you ever see me a post inviting others to come worship the One True Lord and Savior (T), Jesus Christ, please mail me some Aricept.

 

[MurphyClox]

I will restate some of the things that were already said. Anyway, I'll try to keep it short:

1. The terms "full" resp. "partial agonist" resp. "antagonist" are always defined in relation to another ligand. That is very often the natural ligand, but should be more exact defined as the most potent compound at a certain receptor. The natural ligand is not necessarily the most active one. And btw: What is THE natural ligand for opiate receptors?! IIRC, there are more than one natural ligands...

2. You have to consider the second messenger response! That is the biochemical answer inside the cell. In very simple terms, there is always exactly one way for a receptor to be turned "OFF" but there can be more than just one ways for a receptor being turned "ON" (...but there doesn't necessarily have to) . This is a really important feature, because it makes comparison between compounds, who bind to the same receptor by far more difficult. The most common term for this behaviour is "functional selectivity" or "activity".
For example: Consider a ligand that causes to catalyze intracellular response 1 (of 2; lets stay simple for sake of brevity). Consider then a different ligand that causes the same response, but with less potency. No 2 would be, therefore, considered a "partial agonist". Finally, consider a third ligand, who causes intracellular response 2/2. Damn! Although he causes a response, the substance would be considered as an "antagonist"!

3. I'm not sure if you confused this, but just to clear it out: Receptor affinity does NOT equal activity, and thus, does NOT equal potency...

Hope, this helped a bit...

PEACE! Murphy

 

[Enkidu]

First, I am only talking about GPCRs here. I don't have all my scientific terms correct. Hopefully you all will forgive me..

You have to consider the second messenger response! That is the biochemical answer inside the cell. In very simple terms, there is always exactly one way for a receptor to be turned "OFF" but there can be more than just one ways for a receptor being turned "ON" (...but there doesn't necessarily have to) . This is a really important feature, because it makes comparison between compounds, who bind to the same receptor by far more difficult. The most common term for this behaviour is "functional selectivity" or "activity".

I believe you are talking about families of receptors here, correct? Thus, you can have an agonist at one receptor subtype but an antagonist at another. Or is that another type of selectivity?

For example: Consider a ligand that causes to catalyze intracellular response 1 (of 2; lets stay simple for sake of brevity). Consider then a different ligand that causes the same response, but with less potency. No 2 would be, therefore, considered a "partial agonist". Finally, consider a third ligand, who causes intracellular response 2/2. Damn! Although he causes a response, the substance would be considered as an "antagonist"!

Are you sure that you're not mixing physiological results of receptor activation with erm, pharmacological results? For instance, an antagonist initiates NO signal transduction. If there are physiological results from an antagonists binding to the receptor, it is because the antagonist prevents a (possibly endogenous) agonist from activating the receptor.

 

[PsychedelicPeptide]

The short answer is yes, the range of agonism is anything from 0 (antagonist) to 100% (full agonist). Partial agonists can have any value of efficacy greater than 0 and less than 100. A partial agonist is also a partial antagonist. It probably has to do with the ability of the ligand to shift the conformation of the receptor from the inactive to active state. Full agonists shift the equilibrium completely toward the active state, partial agonists shift only partly, and antagonists bind to and stabilize the inactive state.

While I like these descriptions for the most part, I have had a few instances in my own work where I have seen partial GPCR agonists that were not capable of any antagonism. I've also seen things that are something like a 65% antagonist, but also capable of 65+% maximal agonism once you cross the antagonism threshold.

So what I'm trying to say is that defining a partial agonist or partial antagonist is a dicey game as these molecules always display mixed activities and generally each case requires its own context to explain how that particular entity behaves. I generally use the terms full agonist, full antagonist, mixed agonist/antagonist and partial agonist.

 

[MurphyClox]

@Enkidu: Hi fellow! How are ya?

Regarding your first comment:
No, I was not referring to families of receptors but indeed to one and the same receptor (i.e. receptor subtype)! Although the OP requested in particular a discussion of opioid receptors, I clearly remember a discussion about the serotonin-2A-subtype that we had at the dark side. I do also remember that this phenomenon seems to be usual for a wide range of receptors. It can be explained quite easy (that's at least how I understood it): The part of a receptor that faces "outwards" will bind the respective ligand. That certain part won't change throuout time, and therefore, will always accept the same ligands again and again. BUT the coupled G-protein can vary, and thus, can lead to different signaling pathways. Therefore I stated (a bit simplified, I admit) that there are several "ON"-states for a receptor.

Regarding your second statement:
No no, I meant it exactly as I wrote it! I decline in particular this part of yours:

...an antagonist initiates NO signal transduction. If there are physiological results from an antagonists binding to the receptor, it is because the antagonist prevents a (possibly endogenous) agonist from activating the receptor.

This is exactly what I wanted to point out with my post (red marked part): According to the classic (now outdated!!!) definition, an antagonist does indeed not initiate signal transduction, but as research reveals nowadays, most compounds that were once defined as "antagonists" are indeed "inverse agonists"!!! There's a significant difference, because the latter one DOES initiate an intracellular response. The fact that this was not discovered much earlier was due to the difficulty of detecting several signaling pathways in parallel. So, in the classic concept, for almost all receptors there was only one signal tranduction pathway postulated. Just ONE. Every ligand who did reduce the response according to this pathway was therefore considered as an antagonist. But this is only true if you strictly compare the activity to, lets say, the endogenous ligand. As soon as you take more than one signalling pathway into consideration, we have to speak about inverse agonists! Again: This seems to be the regular case and not an exception!

Yours,

Murphy

 

[Enkidu]

@Enkidu: Hi fellow! How are ya?

Hi Murphy! I'm surviving just fine. As you may have guessed, I was unable to come up with the sought-after article. Sorry! I hope you found other means to the information.

Thank you for your remarks. Since I am an autodidact, I need all the pointers I can get! I am reading a book on GPCRs that was published in 2007, and I need to review some of the opening chapters with this information in mind. Maybe I need to get a better book!

 

[PsychedelicPeptide]

Perhaps we need another name to describe the agonists which have a different mode of activation (ie, different G protein activation) than the native receptor ligand then? Non-traditional agonist?

 

[MurphyClox]

Nah! I don't think that there's need for just another term. I would rather think that folks must clear out at the beginning of every discussion, about what exactly they are talking, i.e. at which signal transduction pathway they are looking at... - Murphy

 

[MurphyClox]

I strongly recommend to read Bilz0r's text on neuropharmacology basics! It's a sticky here at Bluelight ADD. That is the current link for the file: <CLICK ME!>

The issue of "functional selectivity" is dealt with, too; search for the term "agonist-directed trafficking" in the file (page 16)! Some very helpful writing!!!

- Murphy

 

[PsychedelicPeptide]

Well given that scientists like to make names for the things they discover and also like to have simple nomenclature methods to distinguish one analog from the next, I think we do need more names for the various styles of agonists and antagonists.

I do foresee potential problems down the road in simply using a single name such as non-traditional agonist as what happens when you have a GPCR with a native full agonist and 2 synthetic non-traditional agonists that cause differential G protein responses themselves?

Sounds like we need the nomenclature to describe what gets activated as well...