Why do we use competitive antagonists like naloxone instead of non-competitive (allosteric) antagonists?

Hm, do you think an allosteric antagonist could be an improvement?

In the drug development a competetive antagonist is usually easier to find than an allosteric antagonist. If that is even possible.

Another thought I m having is. An allosteric inhibitor could not be able to bind while the receptor is in its activated conformation. So that could be a problem, if lets say a drug (opioid) that has very slow dissociation time from the receptor.
 
Another thought I m having is. An allosteric inhibitor could not be able to bind while the receptor is in its activated conformation. So that could be a problem, if lets say a drug (opioid) that has very slow dissociation time from the receptor.
But can naloxone? I was under the impression that competitive antagonists just block receptors they're already bound to, so both the agonist and antagonist are blocking each other's binding.
 
I don't understand your point.

Naloxone competes with reversible competitive agonists for the receptors and its high affinity means there is not much concentration needed. 1.1 nM Ki (wikipedia).

Once bound it stabilizes the inactive conformation of the receptor (and blocking the binding site =antagonism).
 
Naloxone is pretty good I guess, it works, but it won't work well for super high affinity ligands (although as you mentioned this isn't much of an issue since naloxone is high affinity) and massive overdoses. Allosteric antagonists (assuming that they can bind when the agonist is bound, like you mentioned) would work independently of dose and affinity of the agonist.

But yeah that doesn't seem very important now.
 
If the dissociation time is short, then it doesn't matter if our theoretical allosteric inhibitor can bind when the receptor is active.

Also we could find something with higher affinity than naloxone, that is also applicable.
 
Yeah.

Precipitated withdrawal is probably the most important side effect, but allosteric antagonists wouldn't do a great job at reducing this (they could just be silent antagonists instead of silent antagonist/inverse agonist like naloxone), and a low efficacy partial agonist would do a better job.
 
Do not know. There is a lot of factors that can make a drug fail.

Side effects, of course. Or receptors specificity.

And there is probably not the incentive to find a drug that doesn't cause withdrawal like naloxone (instantly). if the drug saves the persons life, it does its job.

So maybe there would be money behind it.

Allosteric and especially irreversible antagonist can be quite problematic. you cant overdose on naloxone.
 
:O what do you mean? irreversible I can see being an issue but I don't know what the problem is with allosteric antagonists.

Kind of sad that people don't care about precipitated withdrawal. I bet people get mistakenly naloxone'd all the time.
 
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