Competitive agonism/antagonism?

[JohnBoy2000]

I thought I recall reading at one point that - an antagonist will always displace an agonist.

Is that correct?

I ask specifically because - Cabergoline is an agonist at several 5HT receptors, and is known to induce depression.

If given with something like Mirtazapine - which blocks many of these receptors - which one wins, basically?

 

[Pomzazed]

Incorrect,

Noncompetitive Antagonist will bind the receptor pocket in prior, so the actual ligand cannot bind anymore.

 

[Coolwhip]

This depends on binding affinity and to some extent dissociation rate. And as Pomzazed is pointing out, it won't literally displace the agonist from the receptor but if the binding affinity is higher it will displace is over time, as the agonist leaves the receptor the agonist takes it place and can prevent it from returning. Ligands with high association/dissociation rates are constantly bouncing around from one receptor to another, like a pinball, and ligands with low dissociation rates grab on and don't let go. So AFAIU you could introduce a ligand with a higher binding affinity than one currently binding to a receptor, but if the current occupant has an extremely low dissociation rate it will still take some time for it to be displaced.

Antagonists may often have higher binding affinities, after all I would guess its Ki needs to be lower than the natural ligand in order for it to be recognized as an antagonist, or at least bind more strongly than the most reference ligands, but intrinsic activity is independent of binding affinity.

 

[JohnBoy2000]

This depends on binding affinity and to some extent dissociation rate. And as Pomzazed is pointing out, it won't literally displace the agonist from the receptor but if the binding affinity is higher it will displace is over time, as the agonist leaves the receptor the agonist takes it place and can prevent it from returning. Ligands with high association/dissociation rates are constantly bouncing around from one receptor to another, like a pinball, and ligands with low dissociation rates grab on and don't let go. So AFAIU you could introduce a ligand with a higher binding affinity than one currently binding to a receptor, but if the current occupant has an extremely low dissociation rate it will still take some time for it to be displaced.

Antagonists may often have higher binding affinities, after all I would guess its Ki needs to be lower than the natural ligand in order for it to be recognized as an antagonist, or at least bind more strongly than the most reference ligands, but intrinsic activity is independent of binding affinity.

The final part/bolded - I don't understand (edit: as in - whether it binds tightly or no, it's still gonna silence the receptor?)
I was under the impression an antagonist basically silenced the post synaptic receptor cascade - or brought it to basal level.

What I recall reading on competitive/non-competitive antagonists is quite hazy but - in any case - antagonist trumps agonist?

Okay so, their Ki values play a role - so on that note;

Cabergoline;

[TABLE="class: wikitable, width: 0"]
[TR]
[TH="bgcolor: #EAECF0, align: center"]Receptor[/TH]
[TH="bgcolor: #EAECF0, align: left"]Binding Affinity (K_i [nM])[/TH]
[TH="bgcolor: #EAECF0, align: center"]Action[/TH]
[/TR]
[TR]
[TD]5-HT_1A[/TD]
[TD]20.0[/TD]
[TD]Agonist[/TD]
[/TR]
[TR]
[TD]5-HT_1B[/TD]
[TD]479[/TD]
[TD]Unknown[/TD]
[/TR]
[TR]
[TD]5-HT_1D[/TD]
[TD]8.71[/TD]
[TD]Unknown[/TD]
[/TR]
[TR]
[TD]5-HT_2A[/TD]
[TD]6.17[/TD]
[TD]Agonist[/TD]
[/TR]
[TR]
[TD]5-HT_2B[/TD]
[TD]1.17[/TD]
[TD]Agonist[/TD]
[/TR]
[TR]
[TD]5-HT_2C[/TD]
[TD]692[/TD]
[TD]Agonist[/TD]
[/TR]
[/TABLE]

Mianserin - all are antagonist or inverse agonist;

​

[TABLE="class: wikitable floatright, width: 0"]
[TR]
[TD]5-HT_1A[/TD]
[TD]400?2,600[/TD]
[TD]Human[/TD]
[TD][/TD]
[/TR]
[TR]
[TD]5-HT_1B[/TD]
[TD]≥2,800[/TD]
[TD]Rat[/TD]
[TD]^[12][/TD]
[/TR]
[TR]
[TD]5-HT_1D[/TD]
[TD]220?400[/TD]
[TD]Human[/TD]
[TD]^[13][14][/TD]
[/TR]
[TR]
[TD]5-HT_1E[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[/TR]
[TR]
[TD]5-HT_1F[/TD]
[TD]13[/TD]
[TD]Human[/TD]
[TD]^[10][/TD]
[/TR]
[TR]
[TD]5-HT_2A[/TD]
[TD]1.6?55[/TD]
[TD]Human[/TD]
[TD]^[15][16][/TD]
[/TR]
[TR]
[TD]5-HT_2B[/TD]
[TD]1.6?20[/TD]
[TD]Human[/TD]
[TD]^[17][18][/TD]
[/TR]
[TR]
[TD]5-HT_2C[/TD]
[TD]0.63?6.5[/TD]
[TD]Human[/TD]
[TD]^[15][19][/TD]
[/TR]
[TR]
[TD]5-HT₃[/TD]
[TD]5.8?300[/TD]
[TD]Rodent[/TD]
[TD]^[20][11][/TD]
[/TR]
[TR]
[TD]5-HT₄[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[/TR]
[TR]
[TD]5-HT_5A[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[TD]ND[/TD]
[/TR]
[TR]
[TD]5-HT₆[/TD]
[TD]55?81[/TD]
[TD]Human[/TD]
[TD]^[21][22][/TD]
[/TR]
[TR]
[TD]5-HT₇[/TD]
[TD]48?56[/TD]
[TD]Human[/TD]
[/TR]
[/TABLE]


Is with respect to Cabergoline inducing depression - again - the physiological outcome associated with activation or blockade of each of those subtypes.....

5ht2a/2c - I know are heteroexpression and control DA/NE release.

Outside of that - as to how cabergoline might induce depression??

 

[Coolwhip]

Intrinsic activity, the thing which determines whether a ligand is an agonist, antagonist, partial agonist, or inverse agonist has nothing to do with binding affinity.

If an agonist has a higher binding affinity than an antagonist it will occupy the receptor site, whether the ligand is an antagonist or not is irrelevant. It seems like antagonists generally have higher binding affinities, but its coincidental, not a hard rule, for example, there are opioid agonists which require special antagonists in the case of accidental exposure and OD because naloxone would not be able to overcome their extremely high binding affinities.

 

[freesolo123]

There are a few on this forum they like to antagonise and displace peoples opinion.

 

[sekio]

Affinity at a site (Ki) is the determinant of whether a compound will bind or be displaced, and is unrelated to intrinsic efficacy.

Higher Ki = weaker binding, more likely to be displaced off the receptor.
Higher efficacy = more drug-type effects.

High affinity, high efficacy (e.g. fentanyl): Binds and displaces other ligands, activates receptor.
High affinity, low efficacy (e.g. naloxone): Binds and displaces other ligands, does not activate or blocks acitivity at receptor.
Low affinity, high efficacy (e.g. dextropropoxyphene): Binds weakly and is displaced by other ligands if present, activates receptor.
Low affinity, low efficacy (e.g. codeine): Binds weakly and does not activate receptor.

Disclaimer: these drugs mentioned are only examples.