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antopsychotics: antagonists?

E

EN21

Bluelighter
Joined
Nov 17, 2005
Messages
139
I have two questions:
Are common antipsychotics like butyrophenones, diphenylbutylpiperidines or the tricyclic ones antagonists or inverse agonists at the dopamine receptors and how can this be distinguished? Do inverse agonists also cause desensitation or internalisation of the receptor?
Has anybody an idea?
 
Complicated question... inverse agonism is an effect best shown in cell culture, and genetically engineered cells expressing high quantities of receptors.

There are some receptors that people have shown to be contitutively active, and hence can have inverse agonists act on them, in whole animals (the histamine H3 receptor), but this is a bit dubious in some peoples eyes.

Ultimately, I don't think it matters too much. Most of these receptors are tonically active, due to activation by neurotransmitters, rather than by their own constitutive means, so the difference between an inverse agonist and an antagonist is largely academic.

Just like antagonists, certain inverse agonists can cause downregulation of certain receptors[1], just as they can cause sensitization [2] and even more complicate differential effects on agonists vs antagonist, [3] (probably reflecting alterations in the binding of G-proteins and the quantity of active-vs-inactive receptor states).
 
so the difference between an inverse agonist and an antagonist is largely academic.
Click to expand...

Well the one agonist/antagonist/inverse agonist spectrum of action I can think of (the benzodiazepines) doesn't strictly follow the above statement as antagonists reverse both the actions of agonists (sedation, amnesia, anticonvulsant) as well as reversing the actions of inverse agonists (alertness, anxiety, hypermnesia & convulsions).

Does the agonist/antagonist/inverse agonist mainly apply to modulatory neurotransmitter sites, such as the benzo receptor where 'normal' status is a Cl- ion channel that's neither to big (agonist) or too small (inv agonist) - a sort of Goldilocks situation!
 
Yeah, but thats cheating because they're ion channels, and the others are GPCRs, and it's double cheating because benzos aren't agonists, but modulators.
 
Fastandbulbous,
Well the one agonist/antagonist/inverse agonist spectrum of action I can think of (the benzodiazepines) doesn't strictly follow the above statement as antagonists reverse both the actions of agonists (sedation, amnesia, anticonvulsant) as well as reversing the actions of inverse agonists (alertness, anxiety, hypermnesia & convulsions).

Does the agonist/antagonist/inverse agonist mainly apply to modulatory neurotransmitter sites, such as the benzo receptor where 'normal' status is a Cl- ion channel that's neither to big (agonist) or too small (inv agonist) - a sort of Goldilocks situation!
Click to expand...

This is a great example, and to me it is the only example that sounds clear. So an benzo antagonist would do -NOTHING- to you if you have not eaten a benzo before, but as BilZOr mentioned, this is all much more complicated with a GPCR, that has an endogenous ligand.
 
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