non-competitive antagonism
Non-competitive antagonism is a block you cannot simply out-shout. No matter how much agonist you pile on, the response stays capped — as if some of the locks have been jammed shut for good and no amount of extra keys can open them.
This insurmountable block can arise in two main ways. An antagonist may bind irreversibly (or very tightly) to the agonist's own site, taking those receptors permanently out of play, or it may bind a separate allosteric site and disable the receptor's machinery so that even a bound agonist cannot fully activate it. Either way, the hallmark on a dose–response curve is a lowered Emax — the plateau itself comes down, not just a rightward shift.
If there is a receptor reserve, an irreversible antagonist may first only shift the curve rightward while the spare receptors absorb the loss; once the reserve is used up, the maximum starts to fall. Because such block often cannot be reversed by competition, recovery may depend on the body synthesising new receptors, which makes these drugs long-acting but harder to titrate.
Phenoxybenzamine binds alpha-adrenoceptors irreversibly; its block of adrenaline cannot be overcome by more adrenaline and lasts until new receptors are made.
Insurmountable block that lowers Emax.
Not all non-competitive antagonists act allosterically and not all allosteric ligands are antagonists; the defining feature here is that the block lowers Emax and cannot be overcome by more agonist.