Talk:Irreversible agonist

Types of agonists - irreversible partial agonists and orthosteric / allosteric distinction

Firstly, there seems to be a difference between orthosteric and allosteric irreversible agonists in the way they modulate receptor function. At least this is what I can assume from reading some literature on the topic.

An orthosteric irreversible agonist of a ligand-gated ion channel causes opening of the ion channel first, and later desensitization of the receptor which keeps the receptor in an unresponsive state until it gets replaced. Thus, by irreversibly binding to the receptor, it only briefly acts as an actual agonist, and for the remaining time functions as an antagonist (or silent agonist, to be more precise).

An irreversible agonist acting on an allosteric binding site doesn't necessarily cause this, as it can either prevent desensitization from happening in the first place, or it allows recovery from the desensitized state while still being bonded to the receptor, and then immediately reactivates the receptor.

An example of the first kind would be Anatoxin A which is an irreversible orthosteric agonist of nicotinic acetylcholine receptors. At the neuromuscular junction it can be nicely observed to cause a depolarization block (a brief period of muscle fasciculations followed by flaccid paralysis).

An example of the second kind seems to be Ivermectin which at higher concentrations can irreversibly activate glycine receptors, even after they have been desensitized by glycine. Indeed, Ivermectin binds to an allosteric site to produce this effect.

Another question concerns irreversible partial agonists: In how far are they different from irreversible full agonists? At least at metabotropic receptors the two should make a difference. At LGIC the two should have differential effects when they are of the second, allosteric type, and keep the receptor cycling between open and desensitized states with different timings or degrees of "openness".

Anatoxin A is an irreversible nicotinic agonist: https://www.sciencedirect.com/science/article/abs/pii/S0041010109004048?via%3Dihub

Ivermectin is an irreversible allosteric agonist at the GlyR: https://pubmed.ncbi.nlm.nih.gov/11278873/

--2003:E7:7706:7A39:D555:E177:3898:75EA (talk) 13:32, 20 May 2022 (UTC)